Human Health and Ecological Risk Assessment 

For the Use of Wildlife Damage Management Methods 

by APHIS-Wildlife Services

Chapter XXVII

USE OF IMMOBILIZATION AND EUTHANASIA DRUGS IN WILDLIFE 

DAMAGE MANAGEMENT

June 2023

Peer Reviewed Final

January 2024
i

EXECUTIVE SUMMARY

The U.S. Department of Agriculture, Animal and Plant Health Inspection Service, Wildlife Services 

(WS) uses immobilization and euthanasia (I&E) drugs to capture, restrain, and euthanize animals 

in wildlife damage management and other wildlife management activities and research. This risk 

assessment is a qualitative evaluation of the risks and hazards to human health, target, and 

nontarget wildlife, fish, and the environment from the use of I&E drugs by WS for mission work. 

This risk assessment evaluates the anesthetics (ketamine hydrochloride, tiletamine 

hydrochloride), sedatives (azaperone, butorphanol tartrate, dexmedetomidine, medetomidine 

hydrochloride, midazolam, nalbuphine, xylazine and combinations thereof), and tranquilizers

(acepromazine, zolazepam) collectively referred to immobilization drugs. It also evaluates

accessory drugs (atipamezole hydrochloride, atropine, doxapram, naltrexone, tolazoline, 

yohimbine hydrochloride) and the euthanasia agents potassium chloride and sodium 

pentobarbital.

WS use patterns, protocols, and label requirements on the use and safety when handling and 

administering I&E drugs minimize the direct and indirect risks to the public and WS applicators. 

WS requires applicators to be trained and certified in the use of I&E drugs before use. WS

applicators typically use hand injection (syringes and syringe poles) and remote darting (dart guns 

and blowpipes) for immobilization and accessory drugs. In contrast, only hand injection is used to 

deliver euthanasia agents. 

The risks to the public from WS I&E drug use are negligible due to the low potential for exposure. 

The public does not have access to WS I&E drugs and is not directly exposed to the drugs during 

or following WS use. Applicators may be at risk of exposure. However, most of the I&E drugs are 

stored in bottles with a septum, which reduces accidental oral, dermal, or inhalation exposure. 

Additionally, a well-trained applicator may miss their target when darting an animal due to 

extenuating circumstances such as an animal moving, but they make every attempt to recover 

darts that missed their target. WS has no records of accidental I&E drug exposure to the public 

or WS applicators. WS follows withdrawal periods and tags animals, per Animal Medical Drug 

Use Clarification Act, and WS Immobilization and Euthanasia Manual guidelines, with ear tags, 

neck collars, or another identifiable mark, indicating they were treated to prevent consumption of 

animals treated with an immobilization or accessory drug; animals may also be disposed of with 

deep burial or another appropriate disposal of euthanized wildlife.

Cumulative impacts on human health are not expected because of the lack of exposure during 

WS applications. The exposure and cumulative risks to ecological resources are negligible for all 

I&E drugs covered in this risk assessment.
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CONTENTS

1 INTRODUCTION................................................................................................................ 9

1.1 I&E Drugs and Other Substances Available for Use....................................................10

1.2 Delivery Methods ........................................................................................................11

1.3 Use Pattern.................................................................................................................12

2 ANESTHETICS.................................................................................................................18

2.1 Ketamine Hydrochloride (e.g., Ketaset®, Vetalar®) ....................................................18

2.1.1 Chemical Description and Product Use................................................................18

2.1.2 Physical and Chemical Properties........................................................................19

2.1.3 Environmental Fate..............................................................................................19

2.1.4 Metabolism ..........................................................................................................20

2.1.5 Hazard Identification ............................................................................................20

2.1.6 Dose-Response Assessment...............................................................................21

2.2 Tiletamine Hydrochloride and Zolazepam (Telazol®)...................................................23

2.2.1 Chemical Description and Product Use................................................................23

2.2.2 Physical and Chemical Properties........................................................................24

2.2.3 Environmental Fate..............................................................................................24

2.2.4 Metabolism ..........................................................................................................25

2.2.5 Hazard Identification ............................................................................................25

2.2.6 Dose-Response Assessment...............................................................................26

3 SEDATIVES......................................................................................................................28

3.1 Azaperone ..................................................................................................................29

3.1.1 Chemical Description and Product Use................................................................29

3.1.2 Physical and Chemical Properties........................................................................30

3.1.3 Environmental Fate..............................................................................................30

3.1.4 Metabolism ..........................................................................................................30

3.1.5 Hazard Identification ............................................................................................30

3.1.6 Dose-Response Assessment...............................................................................32

3.2 Butorphanol ................................................................................................................33

3.2.1 Chemical Description and Product Use................................................................33

3.2.2 Physical and Chemical Properties........................................................................33

3.2.3 Environmental Fate..............................................................................................33
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3.2.4 Metabolism ..........................................................................................................34

3.2.5 Hazard Identification ............................................................................................34

3.2.6 Dose-Response Assessment...............................................................................35

3.3 Dexmedetomidine.......................................................................................................36

3.3.1 Chemical Description and Product Use................................................................36

3.3.2 Physical and Chemical Properties........................................................................36

3.3.3 Environmental Fate..............................................................................................36

3.3.4 Metabolism ..........................................................................................................37

3.3.5 Hazard Identification ............................................................................................37

3.3.6 Dose-Response Assessment...............................................................................38

3.4 Medetomidine Hydrochloride ......................................................................................39

3.4.1 Chemical Description and Product Use................................................................39

3.4.2 Physical and Chemical Properties........................................................................39

3.4.3 Environmental Fate..............................................................................................39

3.4.4 Metabolism ..........................................................................................................39

3.4.5 Hazard Identification ............................................................................................40

3.4.6 Dose-Response Assessment...............................................................................41

3.5 Midazolam ..................................................................................................................42

3.5.1 Chemical Description and Product Use................................................................42

3.5.2 Physical and Chemical Properties........................................................................42

3.5.3 Environmental Fate..............................................................................................43

3.5.4 Metabolism ..........................................................................................................43

3.5.5 Hazard Identification ............................................................................................43

3.5.6 Dose-Response Assessment...............................................................................44

3.6 Nalbuphine .................................................................................................................45

3.6.1 Chemical Description and Product Use................................................................45

3.6.2 Physical and Chemical Properties........................................................................45

3.6.3 Environmental Fate..............................................................................................46

3.6.4 Metabolism ..........................................................................................................46

3.6.5 Hazard Identification ............................................................................................46

3.6.6 Dose-Response Assessment...............................................................................47

3.7 Butorphanol Tartrate, Azaperone, and Medetomidine Hydrochloride (BAMTM)............48

3.7.1 Chemical Description and Product Use................................................................48
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3.7.2 Physical and Chemical Properties........................................................................48

3.7.3 Environmental Fate..............................................................................................48

3.7.4 Metabolism ..........................................................................................................48

3.7.5 Hazard Identification ............................................................................................49

3.7.6 Dose-Response Assessment...............................................................................49

3.8 Nalbuphine, Azaperone, and Medetomidine (NAM) ....................................................49

3.8.1 Chemical Description and Product Use................................................................49

3.8.2 Physical and Chemical Properties........................................................................50

3.8.3 Environmental Fate..............................................................................................50

3.8.4 Metabolism ..........................................................................................................50

3.8.5 Hazard Identification ............................................................................................51

3.8.6 Dose-Response Assessment...............................................................................51

3.9 Xylazine ......................................................................................................................52

3.9.1 Chemical Description and Product Use................................................................52

3.9.2 Physical and Chemical Properties........................................................................53

3.9.3 Environmental Fate..............................................................................................53

3.9.4 Metabolism ..........................................................................................................53

3.9.5 Hazard Identification ............................................................................................53

3.9.6 Dose-Response Assessment...............................................................................55

4 TRANQUILIZERS..............................................................................................................56

4.1 Acepromazine.............................................................................................................56

4.1.1 Chemical Description and Product Use................................................................56

4.1.2 Physical and Chemical Properties........................................................................56

4.1.3 Environmental Fate..............................................................................................56

4.1.4 Metabolism ..........................................................................................................57

4.1.5 Hazard Identification ............................................................................................57

4.1.6 Dose-Response Assessment...............................................................................58

5 ACCESSORY DRUGS......................................................................................................59

5.1 Atipamezole................................................................................................................60

5.1.1 Chemical Description and Product Use................................................................60

5.1.2 Physical and Chemical Properties........................................................................60

5.1.3 Environmental Fate..............................................................................................60

5.1.4 Metabolism ..........................................................................................................60
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5.1.5 Hazard Identification ............................................................................................61

5.1.6 Dose-Response Assessment...............................................................................61

5.2 Atropine ......................................................................................................................62

5.2.1 Chemical Description and Product Use................................................................62

5.2.2 Physical and Chemical Properties........................................................................62

5.2.3 Environmental Fate..............................................................................................63

5.2.4 Metabolism ..........................................................................................................63

5.2.5 Hazard Identification ............................................................................................64

5.2.6 Dose-Response Assessment...............................................................................67

5.3 Doxapram ...................................................................................................................69

5.3.1 Chemical Description and Product Use................................................................69

5.3.2 Physical and Chemical Properties........................................................................69

5.3.3 Environmental Fate..............................................................................................70

5.3.4 Metabolism ..........................................................................................................70

5.3.5 Hazard Identification ............................................................................................70

5.3.6 Dose-Response Assessment...............................................................................71

5.4 Naltrexone ..................................................................................................................71

5.4.1 Chemical Description and Product Use................................................................71

5.4.2 Physical and Chemical Properties........................................................................72

5.4.3 Environmental Fate..............................................................................................72

5.4.4 Metabolism ..........................................................................................................72

5.4.5 Hazard Identification ............................................................................................73

5.4.6 Dose-Response Assessment...............................................................................74

5.5 Tolazoline ...................................................................................................................75

5.5.1 Chemical Description and Product Use................................................................75

5.5.2 Physical and Chemical Properties........................................................................75

5.5.3 Environmental Fate..............................................................................................76

5.5.4 Metabolism ..........................................................................................................76

5.5.5 Hazard Identification ............................................................................................76

5.5.6 Dose-Response Assessment...............................................................................76

5.6 Yohimbine Hydrochloride............................................................................................77

5.6.1 Chemical Description and Product Use................................................................77

5.6.2 Physical and Chemical Properties........................................................................77
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5.6.3 Environmental Fate..............................................................................................78

5.6.4 Metabolism ..........................................................................................................78

5.6.5 Hazard Identification ............................................................................................78

5.6.6 Dose-Response Assessment...............................................................................79

6 EUTHANASIA AGENTS....................................................................................................80

6.1 Potassium Chloride.....................................................................................................80

6.1.1 Chemical Description and Product Use................................................................80

6.1.2 Physical and Chemical Properties........................................................................80

6.1.3 Environmental Fate..............................................................................................81

6.1.4 Metabolism ..........................................................................................................81

6.1.5 Hazard Identification ............................................................................................81

6.1.6 Dose-Response Assessment...............................................................................82

6.2 Sodium Pentobarbital..................................................................................................82

6.2.1 Chemical Description and Product Use................................................................82

6.2.2 Physical and Chemical Properties........................................................................82

6.2.3 Environmental Fate..............................................................................................83

6.2.4 Metabolism ..........................................................................................................83

6.2.5 Hazard Identification ............................................................................................84

6.2.6 Dose-Response Assessment...............................................................................84

7 EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION.......................................85

7.1 I&E Drug Administration..............................................................................................86

7.2 Human Health Exposure and Risk Assessment..........................................................87

7.2.1 Dermal Exposure.................................................................................................88

7.2.2 Injection Exposure ...............................................................................................88

7.2.3 Inhalation Exposure .............................................................................................88

7.2.4 Oral Exposure......................................................................................................88

7.2.5 Risk Characterization of Human Health Exposures..............................................90

7.3 Ecological Exposure and Risk Assessment.................................................................91

7.3.1 Aquatic Exposure Assessment ............................................................................91

7.3.2 Terrestrial Exposure Assessment ........................................................................91

7.3.3 Risk Characterization of Ecological Exposures ....................................................92

8 UNCERTAINTIES AND CUMULATIVE EFFECTS ............................................................93

9 SUMMARY........................................................................................................................94
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10 PREPARERS: WRITERS, EDITORS, AND REVIEWERS.................................................94

10.1 Writers for “Use of Immobilization and Euthanasia Drugs in Wildlife Damage 

Management Risk Assessment”............................................................................................94

Editors/Contributors for “Use of Immobilization and Euthanasia Drugs in Wildlife Damage 

Management Risk Assessment”............................................................................................95

10.2 Internal Reviewers...................................................................................................95

10.3 Peer Review............................................................................................................98

10.3.1 Peer Reviewers Selected by the Association of Fish and Wildlife Agencies.........98

10.3.2 Comments ...........................................................................................................98

APPENDIX 1. Over-the-Counter Antibiotics ............................................................................103

A1.1 Chemical Description and Product Use.......................................................................103

A1.2 Physical and Chemical Properties...............................................................................103

A1.3 Environmental Fate.....................................................................................................103

A1.4 Metabolism .................................................................................................................103

A1.5 Hazard Identification ...................................................................................................103

A1.5.1 Acute Toxicity ..........................................................................................................104

A1.5.2 Sublethal and Chronic Toxicity.................................................................................104

A1.6 Dose-Response Assessment......................................................................................104

A1.6.1 Human Health Dose Response................................................................................104

A1.6.2 Ecological Dose Response ......................................................................................105

APPENDIX 2. FY16-20 Data Tables .......................................................................................106

APPENDIX 3. Chemical Structures.........................................................................................110

REFERENCES .......................................................................................................................114

List of Tables

Table 1a. The annual average volume of anesthetic I&E drugs WS used in WDM activities from 

FY11 to FY15 and FY16 to FY20. .............................................................................................13

Table 1b The annual average volume of sedative I&E drugs WS used in WDM activities from 

FY11 to FY15 and FY16 to FY20. .............................................................................................13

Table 1c. The annual average volume of reversal (accessory drugs) I&E drugs WS used in WDM 

activities from FY11 to FY15 and FY16 to FY20........................................................................13

Table 1d. The annual average volume of I&E drugs WS used in WDM activities from FY11 to 

FY15 and FY16 to FY20. ..........................................................................................................13

Table 2a. The annual average number of animals immobilized with ketamine with or without 

xylazine, by WS in WDM activities from FY11 to FY15 throughout the United States and the final 
viii

disposition of the animal (euthanized or freed). To standardize the data for the table, drugs tracked 

in cubic centimeters were converted to mg of drug used...........................................................14

Table 2b. The annual average number of animals immobilized with tiletamine-zolazepam, with or 

without xylazine, by WS in WDM activities from FY11 to FY15 throughout the United States and 

the final disposition of the animal (euthanized or freed). To standardize the data for the table, 

drugs tracked in cubic centimeters were converted to mg of drug used.....................................14

Table 3a. The annual average number of animals euthanized with potassium chloride euthanasia 

drugs by WS in WDM activities from FY11 to FY15 throughout the United States.....................15

Table 3b. The annual average number of animals euthanized with sodium pentobarbital (sodium 

pentobarbital (390 mg/mL) and Fatal Plus solution) euthanasia drugs by WS in WDM activities 

from FY11 to FY15 throughout the United States......................................................................15

Table 4a. The annual average number of animals recovered with Tolazoline (100mg/mL) alpha2 antagonist drugs by WS in WDM activities from FY11 to FY15 throughout the United States.16

Table 4b. The annual average number of animals recovered with Yohimbine alpha-2 antagonist 

drugs by WS in WDM activities from FY11 to FY15 throughout the United States.....................16

Table 5. States where WS used wildlife drugs for FY11–FY15.... Error! Bookmark not defined.

Table 6. Acute toxicity values for anesthetic drugs and their components.................................18

Table 7. Acute toxicity values for sedative drugs and their components....................................28

Table 8. Acute toxicity values for acepromazine and its components. .......................................58

Table 9. Acute toxicity values for immobilization recovery drugs. ..............................................59

Table 10. Recommended atropine sulfate dosages for animals. ...............................................62

Table 11a. Toxicity doses and effects of atropine in humans: reported lowest dose causing a toxic 

effect (TDLo) and reported lowest dose causing lethality (LDLo). .............................................64

Table 11b. Toxicity doses and effects of atropine sulfate in humans: reported lowest dose causing 

a toxic effect (TDLo) and reported lowest dose causing lethality (LDLo). ..................................65

Table 12. Mammalian toxicity of atropine and atropine sulfate. .................................................65

Table 13. Acute toxicity values for euthanasia drugs.................................................................80

Table 14. WS Method of I&E drug administration......................................................................86

Table 15. Suggested withdrawal times of several immobilization and accessory drugs used in 

free-ranging wildlife and domestic livestock in North America. ..................................................90
INTRODUCTION 9

1 INTRODUCTION

The U.S. Department of Agriculture (USDA), Animal and Plant Health Inspection Service (APHIS), 

Wildlife Services (WS) administer immobilization and euthanasia (I&E) drugs to animals as a 

necessary component of wildlife damage management (WDM) and associated research. During 

the capture and relocation of animals, chemical immobilization can be a valuable method for 

restraining wildlife, decreasing stress, and increasing animal and human safety. Chemical 

immobilization enhances opportunities for personnel to participate in cooperative wildlife research 

and management programs. Chemical immobilization also provides humane options for 

euthanasia. Euthanasia is a necessary tool in WDM, particularly in urban environments where 

human safety is a concern, where zoonotic diseases such as rabies occur, or when an animal is 

injured. WS considers the safety of the animal, personnel, and the public in its decision to use 

and select I&E drugs for mission work.

The Food and Drug Administration (FDA) has regulatory oversite of pharmaceuticals used in 

animals under the Federal Food, Drug, and Cosmetic Act and the Animal Medicinal Drug Use 

Clarification Act (AMDUCA) (21 CFR part 530). Some of these drugs are controlled substances; 

the Drug Enforcement Administration (DEA) has regulatory oversite of their acquisition and 

possession. The Controlled Substances Act, as amended, requires a DEA registration to 

purchase controlled substances and requires complete recordkeeping, proper storage, 

inventorying, and disposal, throughout the lifecycle of use. WS personnel are authorized to use 

approved I&E drugs following completion of the WS training and certification program or other 

approved training. Policies of the WS I&E program comply with DEA and FDA regulations and 

comply with requirements of the states and territories in which personnel administer these drugs.

To ensure appropriate use, storage, and control of I&E drugs, WS established an Immobilization 

& Euthanasia sub-committee under the WS Safety & Health Committee to 1) review and approve 

I&E and accessory (I&E) drugs; and 2) establish training and certification requirements. The

subcommittee approves I&E drugs for WS personnel per WS Directive 2.4301

. WS State Directors 

and Field Station Leaders are responsible for obtaining a state-level controlled substance permit 

(when required and permissible by state law) to obtain DEA registration for procuring and storing

controlled substances needed for mission work. If state law allows only licensed medical 

professionals, including veterinarians, to obtain state-level controlled substance permits, WS 

State Directors and Field Station Leaders can operate under a consulting veterinarian’s 

registration.

State veterinary authorities (on staff or advisory) are involved in the oversight of I&E activities. 

WS establishes procedures in each state for administering drugs used in wildlife capture and 

restraint that are approved by these authorities. Veterinary authorities in each state have 

discretion under AMDUCA to establish withdrawal times (i.e., a period after a drug is administered 

that must lapse before an animal may be used for food) for specific drugs. Animals humans could

consume within the withdrawal period should be marked with ear tags, neck collars, or another 

identifiable mark.

1 WS Directives referenced in this document are found @ http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/wildlifedamage under 

Wildlife Damage – Program Directives
INTRODUCTION 10

This human health and ecological risk assessment (HHERA) qualitatively evaluates potential risks 

and hazards to human health and the environment to exposure from WS use of I&E drugs in 

WDM. The methods used in this HHERA to assess potential human health effects follow standard 

regulatory guidance and methodologies from the National Research Council (1983) and the U.S. 

Environmental Protection Agency (USEPA 2020b) and generally conform to additional Federal 

agency standards. The methods used in the HHERA to assess potential ecological risk to 

nontarget fish and wildlife and the environment generally follow the USEPA (2020b) 

methodologies. This assessment starts with identifying the hazard (problem formulation) and 

evaluates toxicity (the dose-response assessment) and exposure (identifying exposed 

populations and exposure pathways for these populations). Lastly, combining toxicity and 

exposure information provides a determination of adverse human health or ecological risks (risk 

characterization).

I&E drugs and their delivery methods are the primary concerns of this risk assessment. An 

overview of approved drugs, delivery devices, and WS use patterns of substances is provided.

Delivery methods assessed in this document should not be considered an exhaustive evaluation 

of all the delivery methods employed by WS. Risks associated with some delivery methods are 

discussed in greater detail in other WS methods risk assessments, such as the use of firearms

(dart guns), hand capture, and biological sampling (e.g., use of “sharps” - syringe needles, 

scalpels, and other sharp objects), and carcass disposal (disposition of carcasses euthanized

with I&E drugs)2

.

1.1 I&E Drugs and Other Substances Available for Use 

The I&E drugs used by WS represent different categories of pharmaceuticals: 1) anesthetics

(dissociative substances that induce insensitivity to pain), 2) sedatives (substances that induce 

sleep or calmness), 3) tranquilizers (substances that reduce anxiety or tension), 4) accessory 

substances (reversals, antibiotics, or enhancers for other drugs), and 5) euthanasia agents

(substances that induce a humane death). The following are the primary I&E drugs used by WS 

for WDM and associated research:

1. Anesthetics

a. Ketamine hydrochloride (HCl) (e.g., Ketaset®, Vetalar®)

b. Tiletamine HCl + Zolazepam (e.g., Telazol®)

2. Sedatives

a. Azaperone

b. Butorphanol tartrate

c. Dexmedetomidine

d. Medetomidine HCl (e.g., Domitor®)

e. Midazolam

f. Nalbuphine

g. BAM (Butorphanol tartrate, Azaperone, and Medetomidine HCl)

2 Risk assessments on the use of firearms, hand capture and biological sampling, and carcass disposal in wildlife damage 

management are found at https://www.aphis.usda.gov/aphis/ourfocus/wildlifedamage/programs/nepa/ct-ws-risk_assessments and 

discuss those concerns.
INTRODUCTION 11

h. NAM (Nalbuphine, Azaperone, and Medetomidine HCl; NalMed-A) 

i. Xylazine (e.g., Rompun®, CervizineTM, AnaSed®) 

3. Tranquilizers

a. Acepromazine

4. Accessory Drugs/ Substances

a. Atipamezole HCl (e.g., Antisedan)

b. Atropine

c. Doxapram (e.g., Dopram-V®, Dopram®) 

d. Naltrexone

e. Tolazoline HCl

f. Yohimbine HCl

5. Euthanasia Agents

a. Potassium chloride

b. Sodium pentobarbital (e.g., Beuthanasia®-D, Sleepaway®, Fatal-Plus® Solution)

Appendix 1 provides information on some over-the-counter topical antibiotics that WS may use 

during I&E drug applications.

1.2 Delivery Methods

WS personnel may administer I&E drugs by hand or with a remote delivery system. Hand delivery 

involves a syringe or syringe pole (reusable or disposable syringe attached to the end of a long 

handle). Hand syringes are usually used for animals completely restrained chemically (already 

immobilized with a drug) or manually with methods such as a catch pole or sequestration in a 

cage trap. Syringe poles are used for animals restrained loosely, such as in a cage, chute, or 

foothold trap. Remote delivery systems include blowpipes and dart guns (USDA APHIS 2019b). 

Although uncommon, some immobilization (e.g., alpha-chloralose) or sedation drugs (e.g., 

midazolam) may have approved dosage forms for oral administration and could be administered 

to animals in hand baits. 

WS personnel choose the most appropriate delivery method for the situation. Risks associated 

with using a firearm, sharps, and carcass disposal are discussed in other risk assessments and 

not discussed further here, as noted above. 

• Syringes are the standard method for WS to inject I&E drugs into animals. A syringe is a 

simple reciprocating pump consisting of a plunger that fits tightly within a tube called a 

barrel. The plunger can be linearly pulled and pushed along the inside of the tube, allowing 

the syringe to take in and expel solutions through a discharge opening at the front end of 

the tube. The open end of the syringe may be fitted with a hypodermic needle to direct the 

flow into and out of the barrel. 

• Syringe Poles are poles 1.5–5 ft long (445–150 cm) with a syringe at one end. Syringe 

poles, sometimes called jab sticks, may have a thumb button or spring-loaded plunger on 

one end to inject the drug. The syringe pole automatically delivers the drug on contact via 

a plunger or other mechanism but is manually forced. Poles and needles are typically 

made of aluminum and steel, with the syringe made of nylon. Some syringe poles can 

have regular syringes inserted into the tube and used. Syringes can be reusable or 

disposable. Syringe poles are generally used only for immobilization.
INTRODUCTION 12

• Dart Guns (Projectors) generally use compressed air or cartridge blanks to propel a dart 

containing an immobilizing drug. Darts generally consist of a needle and a syringe or 

syringe-like device inside the dart that injects the immobilizing drug into the target animal 

upon impact. WS personnel could use dart guns on the ground or during aerial operations. 

Dart guns generally have an effective range of up to 40 meters, and careful planning and 

extensive practice must be used to properly administer the dose without injuring the 

animal. Dart projectors are generally most effective for immobilizing larger animals such 

as white-tailed deer and bears 3

. 

• Blowpipes (blowguns or blow tubes) also propel a dart containing an immobilizing drug,

but unlike dart guns, blowpipes generally consist of just a long tube about 1–3 meters in 

length. When using a blowpipe, the user propels the dart by placing their mouth over one 

end of the tube and blowing a burst of air into the tube instead of using compressed air or

cartridge blanks to propel the dart to the target. These generally involve a lot of practice 

to generate enough force to propel a dart with accuracy. WS generally uses blowpipes to 

immobilize smaller animals at close range, as their effective range is generally less than 

20 meters.

• Hand Baits may be used to deliver some immobilizing and sedative agents in the future. 

Alpha-chloralose, an immobilization agent that FDA has implemented enforcement 

discretion to allow its use for sandhill cranes under certain conditions and potential for 

additional bird species in the future, is administered via baiting. Due to the limited allowed

use of alpha-chloralose, it is not covered in this risk assessment. Typically, alphachloralose can be made into a paste that can be put on bread, corn, or another substrate 

the target species will eat. Midazolam has approved human drug dosage forms for oral 

administration that veterinarians could prescribe for extra-label use in animals under 

certain circumstances.

1.3 Use Pattern 

WS conducts WDM with a variety of I&E drugs to protect agriculture, property, natural resources, 

and human and animal health and safety throughout the United States. Activities associated with 

management actions are recorded in the WS Management Information System (MIS) 4

. Data from 

FY115 to FY15 and FY16 to FY20 show the use of I&E drugs (Table 1), primarily ketamine, 

xylazine, tiletamine-zolazepam, tolazoline, yohimbine, potassium chloride, and sodium 

pentobarbital in various formulations. New drugs that were used starting in FY17 were 

nalbuphine-azaperone-medetomidine (NAM) and atipamezole. Yohimbine was not used in FY20. 

Tables 1a-d give five-year averages and shows similar usage between the two five-year 

averages, other than the newly added drugs.

WS used ketamine to immobilize 6,091 animals and tiletamine-zolazepam to immobilize 52

3 See the Introduction to Risk Assessments – Chapter I for scientific names. These are only given in this document if not used in that 

Chapter.

4 The MIS (Computer-based Management Information System) is used for tracking WDM activities. Throughout the text, data for a 

year (i.e. FY11 to FY15) will be given and is from the MIS. MIS reports are not be referenced in the text or Literature Cited Section 

because MIS reports are not kept on file. A database is kept that allows queries to be made to retrieve the information needed.

5 FY11 equals the federal Fiscal Year 2011, which is October 1, 2010–September 30, 2011 (the year is denoted by FY11, FY12, and 

so on).
INTRODUCTION 13

animals from FY11 to FY15 (Tables 2a-b). MIS only reports the primary capture method, so 

animals reported as euthanized could have been euthanized using any American Veterinary 

Medical Association (AVMA) approved method. However, most of the 298 animals euthanized

(Tables 2a-b) were likely from euthanasia following immobilization (Tables 3a-b have animals

euthanized, and several are double counted between Tables 2a-b and 3a-b because animals

were immobilized followed by euthanasia). WS euthanizes immobilized animals primarily to obtain 

biological samples (e.g., brainstems to test for rabies) because the animal is suffering due to injury 

or removal as part of management action. It should be noted that FY16–FY20 drug use data are 

included in Tables 1a-d, use of the different drugs by species and state can be found in Appendix 

2.

Table 1a. The annual average volume of anesthetic I&E drugs WS used in WDM activities from 

FY11 to FY15 and FY16 to FY20.

Drug (cc unless noted) Unit of 

Measure

Avg. Amount 

FY11–FY15

Avg. Amount 

FY16–FY20

Ketamine (100 mg/mL) cc 90.3 102.6

Ketamine (200 mg/mL) cc - 15.3

Ketamine/Xylazine 2:1 cc 2.0 -

Ketamine/Xylazine 3:1 cc 1.3 -

Ketamine/Xylazine 5:1 cc 4,405.2 3,333.9

Tiletamine-Zolazepam mg 20,114.4 21,449.3

Table 1b The annual average volume of sedative I&E drugs WS used in WDM activities from 

FY11 to FY15 and FY16 to FY20.

Drug (cc unless noted) Unit of 

Measure

Avg. Amount 

FY11–FY15

Avg. Amount 

FY16–FY20

Nalbuphine-Azaperone-Medetomidine 

(NAM)

cc - 16.6 

Xylazine (100 mg/mL) cc 45.5 43.8

Xylazine (300 mg/mL) cc - 4.2

Table 1c. The annual average volume of reversal (accessory drugs) I&E drugs WS used in WDM 

activities from FY11 to FY15 and FY16 to FY20.

Drug (cc unless noted) Unit of 

Measure

Avg. Amount 

FY11–FY15

Avg. Amount 

FY16–FY20

Atipamezole (5 mg/mL) cc - 19.4

Atipamezole (25 mg/mL) cc - 0.02

Tolazoline (100 mg/mL) cc 17.7 26.5

Yohimbine (2 mg/mL) cc 45.4 22.1

Table 1d. The annual average volume of I&E drugs WS used in WDM activities from FY11 to 

FY15 and FY16 to FY20.

Drug (cc unless noted) Unit of 

Measure

Avg. Amount 

FY11–FY15

Avg. Amount 

FY16–FY20

Potassium Chloride cc 88.5 133.6
INTRODUCTION 14

Drug (cc unless noted) Unit of 

Measure

Avg. Amount 

FY11–FY15

Avg. Amount 

FY16–FY20

Sodium Pentobarbital (Fatal-Plus®

Solution) 

cc 394.4 113.4 

Sodium Pentobarbital (390 mg/mL) cc 8,191.2 3,777.9

Table 2a. The annual average number of animals immobilized with ketamine with or without 

xylazine, by WS in WDM activities from FY11 to FY15 throughout the United States and the final 

disposition of the animal (euthanized or freed). To standardize the data for the table, drugs tracked 

in cubic centimeters were converted to mg of drug used.

Species1 Euthanized Freed Ketamine (mg) Xylazine (mg)

Gray Wolf 0 23 8,118 1,504

Gray Fox 1 9 505 104

Black Bear2 0.4 27 11,802 3,198

Raccoon 167 5,523 331,321 65,950

Striped Skunk 103 200 17,907 3,560

Virginia Opossum** 7 8 769 155

Other Predators (12 spp.)3 3 18 2,406 311

Rodents/Rabbit (4 spp.) 0.6 0.8 24 4

White-tailed Deer (captive)* 0.4 0 173 87

Total (22 spp.)3 282 5,809 373,025 74,873

* Introduced Species ** - Introduced populations Other predator = badger, bobcat, feral cat*, coyote, 

dog*, fisher, red fox, mountain lion, mink, river otter, eastern spotted skunk, and hooded skunk; Rodents/rabbit = 

eastern fox squirrel, eastern gray squirrel, woodchuck, and eastern cottontail. 1 Individual accounts of species are given only for those species that had an annual average of more than 10 taken

except federally listed threatened, endangered, or candidate (T&E) species and eagles are included no matter the 

number. 2 One black bear was treated with ketamine, tiletamine-zolazepam (avg. 200 mg), and xylazine. 3 Other predator species include domestic dogs, a subspecies of the wolf, and thus, not included in the total species 

count. 

Table 2b. The annual average number of animals immobilized with tiletamine-zolazepam, with or 

without xylazine, by WS in WDM activities from FY11 to FY15 throughout the United States and 

the final disposition of the animal (euthanized or freed). To standardize the data for the table, 

drugs tracked in cubic centimeters were converted to mg of drug used.

Species1 Euthanized Freed TiletamineZolazepam (mg) Xylazine (mg)

Gray Wolf 0.8 12 6,414 0

Black Bear2 0 5 2,805 0

- Louisiana Black BearT&E 3 0 2 1,095 0

Grizzly BearT&E 0 2 1,600 0

Other Predators (8 spp.)4 8 4 1,883 0

Feral Swine 6 8 3,470 1,410

Other Ungulates (3 spp.) 0 3 804 804

Eastern Fox Squirrel 1 0 25 0

Total (15 spp.) 16 36 17,966 2,214

* Introduced Species Other predator = badger, coyote, dog*, gray fox, red fox, mountain lion, raccoon, and striped 

skunk; Other ungulate = mule deer, red deer*, pronghorn.
INTRODUCTION 15

1 Individual accounts of species are given only for those species that had an annual average of more than 10 taken 

except federally listed threatened, endangered, or candidate (T&E) species and eagles are included no matter the 

number. 

2 One black bear was treated with ketamine, tiletamine-zolazepam (ave. 200 mg), and xylazine. 3 T&E = Federally listed threatened and endangered species – the Louisiana black bear is no longer listed but included. 4 Other predator species include domestic dogs, a subspecies of the wolf, and thus, not included in the total species 

count.

Tiletamine-zolazepam was used less frequently than ketamine (Tables 2a-b) by WS personnel to 

immobilize animals. It was primarily used for wolves, feral swine, and bears. Xylazine was used 

with tiletamine-zolazepam for ungulates. 

Raccoons (91%) and striped skunks (5%) were the most frequently immobilized species with the 

anesthetic ketamine (Tables 2a-b) and were the most frequent species euthanized with a sodium 

pentobarbital solution (97%) (Tables 3a-b). Raccoons and striped skunks are targets of the 

National Rabies Management Program, where animal use activities support enhanced

surveillance to track the prevalence of rabies in wildlife and monitoring to test animal serum for 

rabies antibodies; brain stems are required for standard rabies diagnosis, which requires the 

animal to be euthanized for postmortem collection of tissue. In summary, 22 species were 

immobilized with ketamine and often accompanied by xylazine, a sedative. 

Tables 3a-b list the animals WS euthanized between FY11 and FY15. The actual number of 

animals euthanized likely is higher, but the take was recorded under another I&E drug in the

database. For example, WS immobilized and euthanized raccoons to collect brainstem tissue 

samples for rabies diagnosis; in the database, only the drug used to immobilize the raccoon was 

recorded with take because only one method can be associated with take, and the drug used for 

euthanasia is listed but not associated with the take of the raccoon. 

Table 3a. The annual average number of animals euthanized with potassium chloride euthanasia 

drugs by WS in WDM activities from FY11 to FY15 throughout the United States.

Species Euthanized Amount Used (cc)

Raccoon 29 76.9

Striped Skunk 5 10.8

Woodchuck 0.2 0.2

Total KCl 34 87.9

Table 3b. The annual average number of animals euthanized with sodium pentobarbital (sodium 

pentobarbital (390 mg/mL) and Fatal Plus solution) euthanasia drugs by WS in WDM activities 

from FY11 to FY15 throughout the United States.

Species1 Euthanized Amount Used (cc)

Virginia Opossum** 226 377.3

Feral/Free-roaming Cat* 55 28.6

Common Gray Fox 15 35.1

Raccoon 462 1,323.9

Striped Skunk 2,980 6,160.6

Other Predator (8 spp.) 12 39.7

California Ground Squirrel 44 24.1

Other Rodent (7 spp.)** 8 7.3
INTRODUCTION 16

Species1 Euthanized Amount Used (cc)

Desert Cottontail 1 0.9

Black-tailed Mule Deer 0.2 1.2

Birds (4 spp.) 2 1.6

Total Sodium Pentobarbital 3,805 8,002.5

* Introduced Species ** - Introduced populations

Other predator – bobcat, coyote**, dog*, red fox**, black bear, hooded skunk, western spotted skunk, long-tailed weasel

Other rodent – beaver**, muskrat, woodchuck, western gray squirrel, eastern fox squirrel**, brown rat*, black rat*

Birds – rock dove*, common barn owl, American kestrel, American crow 1 Individual accounts of species are given only for those species that had an annual average of more than 10 taken.

Between FY11 and FY15, WS used tolazoline or yohimbine on 23 animals to reverse the effects 

of sedatives (Tables 4a-b). All the animals dosed with the antagonist drugs successfully 

recovered. These drugs are rarely used, but they are necessary for certain situations to ensure

animals recover quickly. The two drugs were used on six species, mostly wolves (65%) and feral 

swine (13%). It should be noted that the animals given reversals in Tables 4a-b were also 

immobilized and counted in Tables 2a-b. 

Table 4a. The annual average number of animals recovered with Tolazoline (100mg/mL) alpha2 antagonist drugs by WS in WDM activities from FY11 to FY15 throughout the United States.

Species Freed Drug Used (cc) 

Feral Swine* 3 76.9

Mule Deer 0.8 7.1

Total Tolazoline 3.8 83.0

* Introduced Species

 

Table 4b. The annual average number of animals recovered with Yohimbine alpha-2 antagonist 

drugs by WS in WDM activities from FY11 to FY15 throughout the United States.

Species Freed Drug Used (cc) 

Gray Wolf 15 33.4

Other Predator (3 spp.) 4 4.3

Total Yohimbine 19 37.7

* Introduced Species Other predator = black bear, bobcat, and raccoon 1 Individual accounts of species are given only for those species that had an annual average of more than 10 taken, 

target and nontarget numbers combined. All federally listed threatened, endangered, or candidate species and eagles 

are included.

Table 5 summarizes the WS I&E drugs used by state programs. In all, 38 WS state programs 

used immobilization drugs. Most immobilizing drugs are used for the collection of biological 

samples, where animals are captured in cage traps, immobilized, sampled, and released; 

however, depending on the sample necessary, e.g., blood or brainstem, the animal may or may 

not be euthanized prior to sample collection. It should be noted that rabies was diagnosed in 2%

of the animals tested by enhanced surveillance, and rabies is a lethal disease with a case-fatality 

rate approaching 100%. Animals are also immobilized to apply identification tags or tracking 

collars for monitoring. 

 
INTRODUCTION 17

Table 5. States where WS used wildlife drugs for FY11–FY15.

State Ketamine (mg) Tiletamine-Zolazepam

(mg) Xylazine (mg) Alpha2 Antag. (cc) Euthanasia (cc)

AK - 48 - - 10.7

AL 12,873 - 2,585 - -

AZ 771 600 165 - -

CA 30 - 10 11.3 7,024.4

CO - 2,379 1,254 - -

FL 7,893 - 1,573 0.7 39.7

GA 9,279 - 1,799 - -

ID - 1,800 - - -

KS - 1,100 960 - 56.1

KY 37 - 7 - 0.4

LA - 1,195 - - -

MA 8,685 - 1,679 - -

MD 9,103 - 1,782 - -

ME 13,466 112 3,710 - -

MI 2,345 - 415 7.3 -

MN 4,126 - 492 0.2 -

MO - 1,370 - - -

MS - - - - -

MT - 8,300 - - -

NC 5,750 - 1,141 - -

ND - - - - 4.8

NE - - - - 388.0

NH 2,947 - 591 - -

NJ - - - - -

NV - - - - 38.2

NY 68,169 - 13,671 - 0.8

OH 69,091 - 13,738 - 10.6

OR - 605 - - 31.9

PA 7,973 - 1,585 1.4 14.6

TN 25,405 - 4,936 - 13.4

TX 1,694 100 316 - 22.9

UT - - - - 434.0

VA 27,379 - 5,523 - -

VT 34,304 - 6,872 - 8.8

WA - - - - 1.2

WI 11,279 155 2,165 28.1 -

WV 45,745 - 9,129 - 3

WY 5,051 1,044 1,002 - 10.4

Total 373,395 18,808 77,100 49.0 8,113.9

States 23 13 25 6 19
ANESTHETICS

18

2 ANESTHETICS

WS uses several anesthetics during its WDM activities and associated research. Anesthetics 

produce unconsciousness and loss of pain perception making the target animal unresponsive to 

stimuli (USDA APHIS 2019b). WS uses the anesthetics ketamine and tiletamine (tiletamine is 

used as a combination product of tiletamine and zolazepam) more than the other anesthetics 

available because of their efficacy, cost, and availability. Research indicates the environmental 

fate of residues of injectable anesthetics has not been determined (AVMA 2020). 

The toxicity of anesthetic drugs to the target species, humans, and nontarget species is a primary 

concern. The anesthetics discussed are ketamine, tiletamine/zolazepam, and associated 

products found in these solutions. Table 6 provides toxicity values for these drugs. These values

will be discussed in the following sections on each drug.

Table 6. Acute toxicity values for anesthetic drugs and their components.

Chemical Test Species Test Type LD50 Test Result Reference

Ketamine HCl Brown Rat* Acute oral 447 mg/kg-bw (Zoetis 2014b)

Ketamine HCl House Mouse* Acute oral 617 mg/kg-bw (Zoetis 2014b)

Ketamine HCl Brown Rat* Intravenous 58.9 mg/kg-bw (Zoetis 2014b)

Ketamine HCl House Mouse* Intravenous 55.9 mg/kg-bw (Zoetis 2014b)

Benzethonium 

chloride1

Brown Rat* Acute oral 368 mg/kg-bw (Zoetis 2014b)

Benzethonium 

chloride

Brown Rat* Intravenous 19 mg/kg-bw (Zoetis 2014b)

Benzethonium 

chloride

Brown Rat* Subcutaneous 119 mg/kg-bw (Zoetis 2014b)

Benzethonium 

chloride

House Mouse* Acute oral 338 mg/kg-bw (NCBI 2023k)

Tiletamine2 Brown Rat* Acute oral >5,000 mg/kg-bw (ATE) (Zoetis 2017a)

Mannitol3 House Mouse* Acute oral 22 g/kg-bw (Zoetis 2017a)

Mannitol3 Brown Rat* Acute oral 13,500 mg/kg-bw (Zoetis 2017a)

Zolazepam2 Brown Rat* 

(adult)

Acute oral 398 mg/kg-bw (Zoetis 2017a)

* Domestic laboratory strains

1 Ingredient in ketamine

2 Active ingredient in Telazol

3 Ingredient in Telazol

2.1 Ketamine Hydrochloride (e.g., Ketaset®, Vetalar®)

2.1.1 Chemical Description and Product Use

Ketamine (CAS No. 6740-88-1; C13H16CINO; chemical structure in Appendix 3) is a dissociative 

anesthetic (anesthesia that does not necessarily involve a loss of consciousness) used to 

immobilize wildlife, primarily mammals and birds. It can be administered intramuscularly, 

intravenously, and subcutaneously (EMEA 1997, NCBI 2023f). While its mechanism of action is 

not well understood, this cyclohexanone derivative is thought to block N-methyl-D-aspartate 
ANESTHETICS

19

(NMDA) receptors6 and may also interact with sigma receptors (NCBI 2023f). The drug is used 

to eliminate pain and minimize fear and anxiety. Dissociative anesthetics generally produce 

muscle tension and increased heart rate and can cause excessive salivation and seizures (USDA 

APHIS 2019b). As a result, ketamine is usually combined with other drugs such as xylazine (see 

3. Sedatives below), atropine to reduce salivation or a tranquilizer. The combination of drugs is 

used to anesthetize the animal, maximize reduction of pain and stress, and increase human and 

animal safety. Ketamine can be purchased in 100 mg/mL concentrations under various brand 

names. Ketaset®, Vetalar®, and Ketalar® are the more commonly used brands (WHO 2014). The 

commercially available pharmaceutical form of injectable ketamine consists of 10% ketamine HCl

(CAS No. 1867-66-9), 0.01% benzethonium chloride (CAS No. 121-54-0), and sterile water for 

injection (Zoetis 2014b). Concentrated ketamine can be purchased with a veterinary prescription

through a compounding pharmacy. Ketamine is a DEA Schedule III controlled substance (Kreeger 

and Arnemo 2012, USDA APHIS 2019b). WS uses ketamine, often combined with other drugs, 

for capturing wildlife with dart guns, blowguns, and syringe poles (e.g., for animals incapacitated 

from disease or injuries) or for anesthetizing wildlife with blowguns (typically skunks), syringe 

poles, and hand syringes when already captured using another method, such as cage traps. In 

some cases, oral delivery of ketamine by squirting it into the mouth of an excited animal can calm 

the animal enough to allow injection of an additional drug via the hand or syringe pole (USDA 

APHIS 2019b), which has been used by WS when working with raccoons, skunks, and other 

species caught in box traps (USDA APHIS 2019b). If the animal is removed instead of released, 

ketamine may be used as part of a two-step method prior to administering euthanasia drugs.

Remote delivery does have the possibility of missing the target and ejecting ketamine on the 

ground.

2.1.2 Physical and Chemical Properties

Two enantiomers exist for ketamine: S(+)-ketamine and R(-)-ketamine. The S(+) enantiomer has 

a 3- to 4-fold greater affinity for the NMDA receptor than the R(-) form (WHO 2014). Ketamine 

has a molar mass of 237.727 g/mol and is a white crystalline powder with minimal odor (NCBI 

2023f). Ketamine HCl injection is acidic, with a pH of 3.5 to 5.5. It has a specific gravity of 1.008–

1.028; its solubility in water is 200 g/L (NCBI 2023f, Zoetis 2014b). Its melting point is 92–93°C 

(NCBI 2023f, WHO 2014). Its estimated vapor pressure is 5.15x10-5 mm Hg at 25°C, and the

estimated Henry’s Law Constant is 1.38x10-8 atm-m3

/mol at 25°C (NCBI 2023f). Ketamine has a 

Log Kow 7 of 2.2, indicating it is lipophilic (NCBI 2023f). Ketamine HCl is stable under normal 

storage conditions (Zoetis 2014b). 

2.1.3 Environmental Fate

In China and Taiwan, ketamine is detected widely in surface waters, with major sources from 

hospital and municipal wastewater (Wang et al. 2018). In the United Kingdom, ketamine was 

6 The NMDA receptor is a glutamate receptor and ion channel protein found in nerve cells that is very important for controlling synaptic 

plasticity and memory function.

7 Log Kow is the ratio of the concentration of a solute between water and octanol that is commonly used as a measure of hydrophobicity. 

Substances with high Log Kow values tend to adsorb more readily to organic matter in soils because of their low affinity for water. 

Chemicals with very high Log Kow values (e.g., 4.5) may have the potential to bioaccumulate in an organism.
ANESTHETICS

20

detected in wastewater influent and effluent (Baker and Kasprzyk-Hordern 2013). If ketamine or 

its metabolites enter waterways, the only elimination pathway is photolysis, which generates toxic 

byproducts. One study demonstrated that at higher concentrations, ketamine irradiated by 

sunlight rapidly induces acute biological toxicity in aquatic organisms (Li et al. 2017). 

Phototransformation half-lives for ketamine and norketamine in river waters were 12.4 and 10.1 

hours, respectively (Lin et al. 2014). Lin et al. (2014) found that even though photolysis reduced 

the concentration of ketamine and norketamine (a metabolite of ketamine) in aquatic systems, 

both exhibited higher Microtox® acute toxicity after 14–20 hours of sunlight exposure. In a study 

on the adsorption and degradation of ketamine in four soils, ketamine was reported as likely to be 

mobile in soil (Xega et al. 2019). WS takes precautions to avoid the release of ketamine to aquatic 

environments, such as proper disposal of unused products and carcasses.

2.1.4 Metabolism

Ketamine is not completely metabolized in any species. Ketamine has rapid absorption and 

excretion. Ketamine has a high lipid solubility and low plasma protein binding and, therefore, is 

rapidly absorbed in humans when administered through the intramuscular (Tmax 8 5–15 min), nasal 

(Tmax 20 min), or oral routes (as a solution) (Tmax 30 min). Ketamine is metabolized in the liver and 

intestines, making its bioavailability low when given orally (17%) or rectally (25%) (WHO 2014). 

The liver metabolizes ketamine, and its primary metabolite, norketamine, with enzymes from the 

cytochrome P450 family 9

. Norketamine is 1/3 to 1/2 (or 0.3–0.5) as potent as ketamine (Kim et 

al. 2007, Lin et al. 2014, Wang et al. 2005), and other metabolites include hydroxyl-norketamine 

and dehydronorketamine (Lin et al. 2014). Approximately 90% of a ketamine dose is excreted in 

the urine within 72 hours (WHO 2014). 

Tissue residues of ketamine were studied in horses (Equus ferus caballus), cows, and pigs 

following intravenous or intramuscular injection; animals were slaughtered 24 hours after 

treatment. Ketamine residues could be detected in the liver, kidneys, and in one muscle sample 

of horses (intravenous (IV) treatment). In contrast, one cow (intramuscular treatment) had 

ketamine residues detected in the liver and kidneys. One pig had ketamine residues detected in 

a fat sample. No residues were detected at the injection site or in milk (EMEA 1997). Johnson et 

al. (2023b) measured ketamine residues in raccoons at 2, 4, and 6 days post-immobilization with 

0.096 mL/kg ketamine/xylazine (5:1 mixture of ketamine and xylazine), with one raccoon receiving 

an additional dosage for a final drug dosage of 0.101 +/- 0.011 mL/kg. Ketamine was detected in 

a tissue sample on days 2 and 6.

2.1.5 Hazard Identification

Ketamine is different from most anesthetics because it stimulates the cardiovascular system. 

These effects are not usually problematic but could be fatal in individuals with significant ischemic 

heart disease or high blood pressure (Haas and Harper 1992). In addition, ketamine is a mild 

8 Tmax concentration is the time a drug is at maximum in serum.

9 Cytochromes P450 (CYPs) are a superfamily of enzymes that, in mammals, oxidize steroids, fatty acids, and xenobiotics, and are 

important for the clearance of various compounds and hormone synthesis and breakdown.
ANESTHETICS

21

respiratory depressant, similar to opioids but dissimilar from most anesthetics (WHO 2014). 

Ketamine does not appear to affect reproduction (EMEA 1997).

FDA previously approved ketamine for human use as an analgesic and sedative; however, the 

FDA recently granted breakthrough status to esketamine, a form of ketamine, which could be 

used as an antidepressant (Feller 2016). Ketamine overdoses can cause unconsciousness and 

slowed breathing (DEA 2020). Other adverse effects include hallucinations, blood pressure 

changes, amnesia, lack of coordination, nausea, and respiratory depression. Ketamine produces 

muscle tension that results in staring, exposing the eyes to light and dirt, and requiring the 

application of ophthalmic ointments by WS personnel to protect the eyes of anesthetized animals

(USDA APHIS 2019a).

2.1.5.1 Acute Toxicity

For acute oral toxicity or LD50 10, ketamine is a toxicity category II for rats with an oral LD50 of 447 

mg/kilograms of body weight (kg-bw) and toxicity category III for house mice with an LD50 of 617 

mg/kg-bw (Table 6). Ketamine is more acutely toxic when given intravenously, with an LD50 of 

58.9 mg/kg-bw in rats and 55.9 mg/kg-bw in mice (Table 6). The ketamine HCl injection 

formulation is an eye and skin irritant in rabbits (Zoetis 2014b).

2.1.5.2 Sublethal and Chronic Toxicity

Rats receiving 10 mg/kg/day ketamine HCl intravenously for 6 weeks had a no observed adverse 

effect level (NOAEL) at the maximum dose (Acosta-Jamett et al. 2010); however, there was a 

slight but not significant decrease in food intake and moderate weight gain depression (EMEA 

1997). Similarly, dogs receiving 40 mg/kg-bw/day ketamine HCl intramuscularly for 6 weeks also 

resulted in a NOAEL (Pfizer 2008), but they did have slight weight loss or anorexia (EMEA 1997). 

Ketamine HCl was not found to be teratogenic for rats (NOAEL of 120 mg/kg/day, intramuscular), 

rabbits (NOAEL of 24 mg/kg-bw/day, intramuscular), and mice (NOAEL of 300 mg/kg-bw/day, 

intravenous) (Zoetis 2014b). In another study, histopathological changes in rat fetuses were 

observed at doses 10 times those used in humans for anesthesia (WHO 2014), while a study in 

female dogs injected with 25 mg/kg-bw intramuscularly 6 times during one trimester of pregnancy 

did not show adverse effects (EMEA 1997). The WS use of ketamine in the anesthesia of wildlife 

would not subject individual animals to consecutive, multi-day dosages.

2.1.6 Dose-Response Assessment

2.1.6.1 Human Health Dose Response

Ketamine has very strong analgesic and neuroleptic effects in humans. Ketamine is typically 

administered intravenously at an induction dose of 0.5–1.5 mg/kg-bw, but it can also be 

administered intramuscularly (4–6 mg/kg-bw) or rectally (8–10 mg/kg-bw)(Brunton and Knollmann 

2022). At induction doses, blood pressure, and heart rate increase initially, while respiration rate 

10 LD50 is the Lethal Dose of 50% (one half) of a group of test animals. The LD50 is one way to measure the short-term poisoning 

potential, the acute toxicity, of a material.
ANESTHETICS

22

stays the same. Side effects include hallucinations and impeded psychomotor functions for 

several hours after a single injection (EMEA 1997). Evidence suggests that the margin of safety 

with ketamine overdose is wide. Adverse outcomes were not observed in nine healthy children 

treated in the emergency room that accidentally received 5 to 100 times the intended dose of 

ketamine (Green et al. 1999). Liver damage could occur if prolonged or repeated use of ketamine 

occurs. In one study, six patients were scheduled to receive two continuous intravenous 100-hour 

S(+)-ketamine infusions (infusion rate 10–20 mg/hour) 16 days apart. Three individuals developed 

hepatotoxicity (liver failure) after the second infusion began (WHO 2014). The WHO (2014) found 

a dose above 11.3 mg/kg-bw intravenously may be lethal to humans; for a 60 kg person, this is 

equivalent to an intravenous dose above 680 mg.

Data on human exposure to ketamine during pregnancy is not available, but clinical evidence 

suggests that ketamine may depress fetal functions when 2 mg/kg-bw (intravenous) is 

administered (WHO 2014).

2.1.6.2 Ecological Dose Response

Intravascular injection of 30 mg/kg-bw ketamine into adult Coho salmon (Oncorhynchus kisutch)

and juvenile rainbow trout provided anesthesia. Still, the length of anesthesia differed between 

the species, likely based on fish size (Graham and Iwama 1990). Anesthesia lasted for up to 4 

hours for Coho salmon and 1 to 2 hours for trout. After injection, the fish experienced an 

interruption in ventilation, which created hypoxia and acidosis; however, the fish normalized as 

ventilation was restored naturally. Under anesthesia, the fish did not show swimming behavior,

and some fish lost balance. In the initial seconds after injection, the fish exhibited struggling, with

researchers suspecting observed elevated CO2 and depressed O2 as the cause. In another study, 

rainbow trout injected intramuscularly with 130 mg/kg-bw and 150 mg/kg-bw ketamine were 

anesthetized for 20 minutes and 50 to 80 minutes, respectively. However, the recovery period 

was long, lasting up to 90 minutes, and the fish displayed ataxia and excitement (Oswald 1978).

In aquatic invertebrates, a 20 mg/kg-bw dose of ketamine was injected into the hemolymph of 

blue crab (Callinectes sapidus) gave short-term (under 10 minutes) light anesthesia (Quesada et 

al. 2011). The criteria for light anesthesia were a loss of righting reflex and defensive response, 

slow and occasional limb movement, and slow limb withdrawal when pressed with forceps. 

Bradycardia (slower than normal heart rate) was an observed side effect, but the crab’s heart rate 

approached baseline within 10 minutes. An intramuscular dose of 90 μg/g-bw of ketamine 

provided deep anesthesia in virile crayfish (Faxonius (Orconectes) virilis) for one hour or longer 

(Brown et al. 1996). Crayfish fully recovered from anesthesia, and no adverse effects were noted.

In black bears, an estimated 6.9 +/- 0.4 mg/kg-bw ketamine, along with 3.5 +/- 0.2 mg/kg-bw

xylazine was administered using a syringe pole (n=9) or dart (n=1) to immobilize the animals 

(Williamson et al. 2018). Bears were approachable at a mean time of 7.6 minutes. The bears had 

a higher heart rate but did not exhibit hyperthermia. During recovery and following the reversal

with yohimbine, the bears exhibited incoordination and ataxia while trying to walk. The bears were 

then monitored for over six months, and no mortality or unusual movements were noted during 

this time (Williamson et al. 2018). 
ANESTHETICS

23

Cardiovascular and behavioral responses were evaluated in adult gray wolves administered 6.6 

mg/kg-bw ketamine and 2.2 mg/kg-bw xylazine intramuscularly by hand or syringe pole (Kreeger 

et al. 1987). Induction time averaged 4.6 minutes. The animals experienced bradycardia and 

hypertension.

Telesco and Sovada (2002) evaluated doses of ketamine and xylazine to determine a dosage 

appropriate to immobilize swift foxes. In three trials, they evaluated dosage ratios of 2.27:1.2, 

5.68:1.2, and 11.4:1.2 mg/kg-bw ketamine and xylazine, respectively. In a fourth trial, they 

evaluated a higher dosage of 11.4:2.4 mg/kg-bw ketamine and xylazine. Induction and recovery 

were smooth, and the induction times and recovery periods were similar for the dosages in the 

first three trials. However, the immobilization time increased with the increase in dose. Foxes in 

trials 1 and 2 had increased salivation, compulsive licking, vomiting, and muscle twitching. Heart

rate and respiratory rate were depressed but were within the range established for domestic 

canids. The authors suggest a dosage of 10 mg/kg-bw ketamine and 1 mg/kg xylazine for a 

handling time of 40 minutes.

In male and female pigeons, 30 mg/kg-bw ketamine was administered intramuscularly to evaluate 

the drug’s clinical effects (Azizpour and Hassani 2012). The induction time averaged 4.50 

minutes, and the anesthesia duration averaged 8.13 minutes. The birds displayed poor muscle 

relaxation. Recovery was reported as “stormy”; birds displayed severe convulsions and wing 

flapping.

In laboratory snakes (unspecified), 50 mg/kg-bw ketamine given intramuscularly provided 

sedation/analgesia within 10 minutes, peaking at 30 minutes, lasting 60 minutes, and taking less 

than 72 hours to reach complete recovery (Green et al. 1981). Snakes maintained muscular tone 

and exhibited slow writhing movement when handled. In raptors, 15 mg/kg-bw ketamine was

given intramuscularly into the pectoral muscles, with an onset of sedation/analgesia in 3 minutes, 

reaching peak effect in 7 minutes and attaining full recovery within 1–5 hours (Green et al. 1981). 

A ketamine dose of 20–50 mg/kg-bw intramuscularly or intravenously or 15–20 mg/kg-bw

provides chemical restraint in rabbits (Plumb 2018). In horses, a dose of 2 mg/kg-bw of ketamine 

given intravenously after administering a sedative (xylazine or xylazine and butorphanol) provides 

anesthesia in the field (Plumb 2018). In swine, ketamine doses range from 11 mg/kg-bw to 22 

mg/kg-bw, given intramuscularly (Plumb 2018).

2.2 Tiletamine Hydrochloride and Zolazepam (Telazol®)

2.2.1 Chemical Description and Product Use

Telazol® is a mixture of tiletamine (an anesthetic) and zolazepam (a tranquilizer), which selectively 

interrupts association pathways to the brain. Tiletamine (CAS No. 14176-50-2; C12H17NOS; 

chemical structure in Appendix 3) is a dissociative anesthetic like ketamine but is 2.5–5 times 

more potent. It also generally works faster and lasts longer (Fowler and Miller 1999, USDA APHIS 

2019b). Tiletamine can only be purchased as Telazol (NCBI 2023b). Telazol consists of 50 mg/mL 

zolazepam HCl (CAS No. 33754-49-3; C15H16CIFN4O; Appendix 3), 50 mg/mL tiletamine HCl, 
ANESTHETICS

24

less than 6% mannitol (CAS No. 69-65-8), and sterile water for injection (Zoetis 2019). Zolazepam 

is a benzodiazepine derivative tranquilizer that minimizes the muscle tension and seizures 

associated with tiletamine (Cording et al. 1999). Muscle tension from Telazol is variable in 

different animal species; it produces extensive muscle tension in dogs but has a more relaxed 

response in coyotes, wolves, and bears (Fowler and Miller 1999, USDA APHIS 2019b). The small 

volume required for dosing, ease of administration, wide safety margin, and dose-related effects, 

as well as it being a DEA Class III controlled substance, make Telazol a popular anesthetic drug

for WS WDM activities. WS uses Telazol in wildlife capture and anesthesia with all types of

delivery methods, including remote delivery with dart guns to direct hand-injection via syringe 

where possible. Remote delivery does have the possibility of missing the target and ejecting 

tiletamine and zolazepam on the ground.

2.2.2 Physical and Chemical Properties

Telazol, a 1:1 mixture of tiletamine and zolazepam, is sold as an off-white powder and must be 

reconstituted with sterile water before use. After it is reconstituted, the shelf life is seven days at 

room temperature and 56 days if refrigerated (Zoetis 2017a). Telazol is slightly soluble in water 

(Zoetis 2017a). 

Tiletamine has a water solubility of 0.0965 mg/ml (DrugBank 2021e). Its estimated vapor pressure 

is 1.86x103 mm Hg at 25oC, and the estimated Henry’s Law constant is 1.34x10-8 atm-cu m/mol 

at 25°C (NCBI 2023b). The estimated log Kow for tiletamine is 2.79, indicating that it is a lipophilic 

drug (DrugBank 2021e). It is considered acidic, with a pH ranging from 3.5 to 5.5. Its boiling point 

is 100°C, and its density is 1.52. It is stable under normal use conditions. Tiletamine’s estimated 

bioconcentration factor is 15.8 (USEPA 2023b).

Zolazepam is a crystalline structure. Its estimated pKa is 4.69 (USEPA 2023a). Its predicted water 

solubility is 269 mg/L (DrugBank 2021d). Its predicted vapor pressure is 1.05x10-8 mmHg, log 

Kow is 1.56, Henry’s Law Constant 1.33x10-9 atm-m3

/mol, and melting point is 181°C (USEPA 

2023a). Zolazepam’s estimated bioconcentration factor is 18 (USEPA 2023a).

2.2.3 Environmental Fate

Little information and research are available on tiletamine and zolazepam's environmental fate or 

transport. This is because the direct environmental release is unlikely except for a missed dart; 

the drug is administered to animals through injection. The USEPA predicted that the 

biodegradation half-life (DT50) in soil for tiletamine is 4.07 days and for zolazepam is 3.36 days 

(USEPA 2023a); however, no experimental data are currently available. Tiletamine is soluble in 

water and based on its estimated vapor pressure and Henry’s law constant, it is not considered 

volatile. Due to the pharmaceutical drug approval process, environmental fate studies are limited. 

Telazol, equal parts tiletamine and zolazepam, is not classified as environmentally hazardous. 

Both tiletamine and zolazepam have bioconcentration factors that indicate very low 

bioconcentration potential in aquatic environments. As with many compounds, large and frequent 

spills may have harmful or damaging effects on the environment. Releases into the environment 
ANESTHETICS

25

of Telazol, tiletamine, or zolazepam should be avoided. Data are not available concerning the 

environmental degradability, nor are data available concerning the bioaccumulative potential or 

soil mobility of Telazol. Adverse environmental effects such as ozone depletion, photochemical 

ozone creation potential, endocrine disruption, and global warming potential are not expected 

from this component (Zoetis 2017a).

2.2.4 Metabolism

Telazol is a non-narcotic, non-barbiturate, injectable anesthetic. The onset of anesthesia 

generally occurs within 5 to 12 minutes (Zoetis 2019). Muscle relaxation is optimum for the first 

20 to 25 minutes and then diminishes (USDA APHIS 2013, Zoetis 2019). If administered

intravenously, anesthesia lasts 15–20 minutes, whereas if administered intramuscularly,

anesthesia lasts 30–45 minutes (West et al. 2007). Tiletamine, one of the two drugs in Telazol,

has a high lipid solubility and is rapidly absorbed through the intramuscular route (Riviere and 

Papich 2009). Little information is available regarding the enzymatic pathways involved in the 

metabolism of tiletamine and zolazepam (Kumar et al. 2006). Species metabolize Telazol

differently and subsequently have differing recoveries. In pigs administered 10 mg/kg-bw Telazol 

(1:1 ratio of tiletamine and zolazepam) intramuscularly, the elimination half-life was 3.7 and 8.4 

hours for tiletamine and zolazepam, respectively (Kumar et al. 2006). Zolazepam takes longer to 

metabolize in cats, while tiletamine takes longer to metabolize in dogs. According to the Telazol 

product label, the elimination half-life for tiletamine and zolazepam administered intravenously in 

dogs is 0.87 hours and 0.41 hours, respectively (Zoetis 2019). In black bear, concentrations of 

tiletamine and zolazepam (Telazol) in the serum, liver, muscle, and urine were measured 3, 7, 

14, and 21 days after administration of 500 mg Telazol, except for two bears that required 1,000 

mg and 1,250 mg Telazol (Ryan et al. 2009). Tiletamine was not detected on day 14, and 

zolazepam was not detected on day 21; on day 14, only two bears had detectable levels of 

zolazepam in the urine (Ryan et al. 2009). The authors found black bears quickly metabolize and 

eliminate Telazol to undetectable levels within 7–14 days. Animals differ in their recovery 

response. Pigs awaken slowly and calmly, while horses can have an agitated recovery if they are 

not provided with additional sedation (Riviere and Papich 2009).

2.2.5 Hazard Identification

FDA-approved Telazol for use in dogs and cats; however, the drug is widely used as an anesthetic

agent for wildlife. Tiletamine is labeled as harmful if swallowed or inhaled (NCBI 2023b). 

Zolazepam is labeled as a skin, eye, and respiratory irritant (NCBI 2023s). Telazol can cause 

staring, which can expose the eyes to light and dirt and cause the eyes to dry out, requiring the 

application of ophthalmic ointments by WS personnel to protect the eyes of anesthetized animals

(USDA APHIS 2019b). The Telazol product label indicates there may be pain upon intramuscular

injection, particularly in cats (Zoetis 2019).

Telazol is not known to be carcinogenic (Zoetis 2017a). The SDS classifies Telazol as 

reproductive toxicity (i.e., to an unborn child) category 2, although no data are accessible to 

support this classification (Zoetis 2017c). However, zolazepam, an active ingredient in Telazol, 
ANESTHETICS

26

did not have reproductive effects in adult rats exposed to doses up to eight times the therapeutic 

dose (Lin et al. 1993).

2.2.5.1 Acute Toxicity

Telazol has an oral acute LD50 >5,000 mg/kg-bw in the rat (Zoetis 2017c). Mannitol, an ingredient 

in Telazol, has an oral LD50 of 22 g/kg-bw and 13,500 mg/kg-bw in the mouse and rat, respectively 

(Zoetis 2017c). Tiletamine is a category IV for acute oral toxicity in adult rats (LD50 >5,000 mg/kgbw), whereas zolazepam is a category II (Oral LD50 of 398 mg/kg-bw; Table 6).

2.2.5.2 Sublethal and Chronic Toxicity

Information is limited on the sublethal and chronic toxicity of Telazol. Zolazepam has a lowest 

observed adverse effect level ((LOAEL); 3-month study) of 10 mg/kg-bw/day in the dog and 

monkey and a no observed adverse effect level (NOAEL) of 10 mg/kg-bw/day in the rat (Zoetis 

2017c). In a study in rabbits, 32 or 64 mg/kg-bw Telazol was administered intramuscularly, and 

the anesthesia effects were monitored (Brammer et al. 1991). Seven days post-injection, renal 

tubular necrosis was present in all high-dose rabbits and three rabbits in the low-dose group, 

indicating that Telazol is nephrotoxic at both doses and did not produce analgesia.

2.2.6 Dose-Response Assessment

2.2.6.1 Human Health Dose Response

Human toxicity data for Telazol is limited due to its FDA-approved use exclusively in veterinary 

medicine. Telazol causes rapid anesthetic effects, but sudden alertness is not uncommon as the 

effects of the drug subside (Quail et al. 2001). In one case report, a female survived injecting 

herself with an estimated 200 mg of Telazol, or 100 mg of each ingredient, based on the 2 mL 

missing from a Telazol vial (Quail et al. 2001). The authors describe this dose as similar to the 

3.6 mg/kg-bw given to chimpanzees for anesthesia. The subject of the case report also used 

diazepam, making it difficult to attribute subsequent symptoms to Telazol exposure. She was 

obtunded and hypotensive but had a gag reflex, which is consistent with Telazol effects but could 

also be effects from diazepam. There are two reports of death caused by self-injected drug 

intoxication of Telazol (Chung et al. 2000, Cording et al. 1999). In one case, a male self-injected 

Telazol and ketamine (Cording et al. 1999). This male had postmortem concentrations of 

tiletamine in the blood, urine, and liver of 295 ng/mL, 682 ng/mL, and 196 ng/g, respectively, and 

zolazepam concentrations in the same tissue of 1.71 ng/mL, 1.33 ng/mL, and 15.5 ug, 

respectively (Cording et al. 1999). The concentration of ketamine was 37 ng/mL and 381 ng/mL 

in the blood and urine, respectively. The authors did not estimate the amount of Telazol selfadministered. In another case, a male had concentrations of 0.85 mg/L tiletamine and 3.3 mg/L 

zolazepam in the blood (Chung et al. 2000). Injection-site tissue has 25.1 mg/kg tiletamine and 

23.3 mg/kg zolazepam (Chung et al. 2000). The authors did not estimate the amount of Telazol 

self-administered.
ANESTHETICS

27

Similarly, data on the human toxicity of tiletamine and zolazepam independently is lacking.

However, since tiletamine belongs to the same class of drugs as ketamine, it can be assumed 

that the pharmacokinetics between these drugs is similar (Cording et al. 1999). Tiletamine has 

the potential to affect the central nervous system in humans. Adverse effects include dizziness, 

light-headedness, headache, nausea, and blurred vision (NCBI 2023b).

2.2.6.2 Ecological Dose Response

Animal studies have shown that the acute induction intramuscular dose for Telazol (1:1 

tiletamine:zolazepam) in dogs is 6.6 to 9.9 mg/kg-bw at a maximum dose of 13.6 mg/kg-bw, and 

in cats, 9.7 to 11.9 mg/kg-bw at a maximum intramuscular dose of 32 mg/kg-bw (Dechra 

Veterinary Products LLC 2020). In monkeys, 50 mg/kg-bw intravenously (intravenous) causes 

brief and mild clonic seizures (Lin et al. 1993). 

The lowest observed adverse effect level (LOAEL) for zolazepam in dogs and monkeys was a 

dosage of 10 mg/kg/day for three months (route of administration not provided) (Zoetis 2017c). 

Central nervous system toxicity was associated with treatment for monkeys, and both central 

nervous and gastrointestinal system toxicity was associated with dogs (Zoetis 2017a). A study 

involving four cats anesthetized with 20 mg/kg of tiletamine (route of administration not provided)

between days 10 and 50 of gestation produced normal offspring (Zoetis 2013).

In aquatic invertebrates, a 30 mg/kg-bw dose of tiletamine-zolazepam injected into the 

hemolymph of blue crab (Callinectes sapidus) gave short-term (under 10 minutes) deep 

anesthesia (Quesada et al. 2011). Bradycardia was an observed side effect, but the crab’s heart 

rate approached baseline within 10 minutes.

In iguanas, an intramuscular injection of 10.53 ± 4.2 mg/kg-bw tiletamine-zolazepam caused 

immediate but not excessive excitement, followed by muscle relaxation a few minutes later 

(Mauthe von Degerfeld 2004). The mean induction time was 6.5 minutes, with a recovery time of 

around 45 minutes. Respiratory rates decreased, and cardiac rates increased slightly (Mauthe 

von Degerfeld 2004). 

In yellowtail amberjack (Seriola lalandi), an oral dose of 8–9 mg/kg-bw tiletamine-zolazepam 

caused sedation that lasted a maximum of 12 hours. These fish were responsive to the touch and 

recovered between 12 and 48 hours after dosing. Four of the 14 fish died due to the unplanned 

consumption of additional oral doses (as cited in (West et al. 2007)). Goldfish, given 50 mg/kgbw ketamine by gavage, reached full sedation after 30 minutes (Raines and Clancy 2009). Both 

river stingray (Potamotrygon motoro) and wipers (hybrid striped x white bass (Morone saxatilis x 

M. chrysops)) reached light sedation (loss of equilibrium, very slow swimming, loss of muscle 

tone) at 20 mg/kg-bw and 300 mg/kg-bw by oral route, respectively (Raines and Clancy 2009).
SEDATIVES 28

3 SEDATIVES 

WS uses sedatives in conjunction with anesthetics such as ketamine and Telazol to calm animals 

prior to euthanasia, relocation, placing a radio collar on the animal for tracking, collection of 

biological samples, and other WDM activities, especially where the safety of people and animals 

is a concern. Sedatives cause drowsiness, muscle relaxation, and central nervous system 

depression more than tranquilizers while reducing anxiety and producing calm with the animal 

awake. WS may use the sedatives azaperone, butorphanol, dexmedetomidine, medetomidine 

HCl, nalbuphine, xylazine, or a combination of these.

The sedatives WS administers to animals have central and/or peripheral nervous system effects. 

Primary effects include sedation, analgesia, bradycardia, respiratory depression, mild 

hypotension, and a reduction in antidiuretic hormone. Peripheral effects include vasoconstriction, 

which can lead to hypertension and reduced gastrointestinal movements (Clarke and England 

1989). 

The toxicity of sedative drugs to the target species, people, and nontarget species is a primary 

concern. Table 7 gives toxicity values for sedative drugs. These are discussed in the following 

sections on each drug or combination of drugs. Toxicity data were available for the sedatives 

azaperone, butorphanol, dexmedetomidine HCl, medetomidine HCl, nalbuphine HCl, and 

xylazine. 

Table 7. Acute toxicity values for sedative drugs and their components.

Chemical Test Species Test Type LD50 Reference

Azaperone Guinea Pig* Acute oral 202 mg/kg-bw (NCBI 2023c)

Azaperone House Mouse* Acute oral 385 mg/kg-bw (NCBI 2023c)

Azaperone Brown Rat* Acute oral 245 mg/kg-bw (NCBI 2023c)

Azaperone House Mouse* Intravenous 42 mg/kg-bw (NCBI 2023c)

Azaperone Brown Rat* Intravenous 25 mg/kg-bw (NCBI 2023c)

Azaperone Brown Rat* Intravenous 28.1 mg/kg-bw (Pitman-Moore 1982)

Azaperone House Mouse* Subcutaneous 179 mg/kg-bw (NCBI 2023c)

Azaperone Brown Rat* Subcutaneous 450 mg/kg-bw (NCBI 2023c)

Azaperone House Mouse* Intraperitoneal 63 mg/kg-bw (NCBI 2023c)

Butorphanol tartrate Dog Acute oral >50 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate Monkey^ Acute oral >50 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate House Mouse* Acute oral 395 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate Brown Rat* Acute oral 315 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate Dog Intravenous 10 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate House Mouse* Intravenous 36 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate Brown Rat* Intravenous 17 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate House Mouse* Subcutaneous 299 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate Brown Rat* Subcutaneous 425 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate Dog Intramuscular 17 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate House Mouse* Intramuscular 208 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate Brown Rat* Intramuscular 255 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate House Mouse* Intraperitoneal 192 mg/kg-bw (NCBI 2023w)

Butorphanol tartrate Brown Rat* Intraperitoneal 127 mg/kg-bw (NCBI 2023w)

Dexmedetomidine HCl Dog Intravenous 2 mg/kg-bw (Zoetis 2017b)
SEDATIVES 29

Chemical Test Species Test Type LD50 Reference

Midazolam Brown Rat* Oral 1600 mg/kgbw (NCBI 2023u)

Midazolam Brown Rat* Intravenous 75 mg/kg-bw (NCBI 2023u)

Midazolam Brown Rat* Intramuscular >50 mg/kg-bw (NCBI 2023u)

Midazolam House Mouse* Oral 1600 mg/kgbw (NCBI 2023u)

Midazolam House Mouse* Intramuscular >50 mg/kg-bw (NCBI 2023u)

Midazolam House Mouse* Intravenous 50 mg/kg-bw (NCBI 2023u)

Medetomidine HCl Brown Rat*, 

Adult Acute oral 31 mg/kg-bw (UK Competent Authority 2014)

Medetomidine HCl

Water Flea 

(Daphnia 

magna)

48 Hr EC50

acute 

immobilization

4.5 mg/L

Bätscher, 2007b in (UK 

Competent Authority, 

2014)

Medetomidine HCl

Pacific Oyster 

(Crassostrea 

gigas)

48 Hr EC50

embryo-larval 

development

2.5 mg/L

Fox and Sharpe, 2012 

in (UK Competent 

Authority, 2014)

Nalbuphine HCl Dog Acute oral 1100 mg/kgbw (NCBI 2023m)

Nalbuphine HCl Dog Intravenous 140 mg/kg-bw (Hospira 2019)

Xylazine Brown Rat*, 

Adult Acute oral 130 mg/kg-bw As cited in (IPCS 2015)

Xylazine Water Flea 48 Hr EC50 >18 mg/L (University of 

Hertfordshire 2018a)

* Domestic laboratory strains ^ Species not known – not in source document 

3.1 Azaperone

3.1.1 Chemical Description and Product Use

Azaperone (CAS No. 1649-18-9; C19H22FN3O; chemical structure in Appendix 3) is a sedative and 

works by depressing nerve functions. It belongs to the class of butyrophenones, with most drugs 

in this class being antipsychotic drugs. Azaperone blocks dopamine receptors in the brain and, at 

low doses, is an alpha-receptor blocker (Mestorino et al. 2013). This effect decreases the animal’s 

response to external signals and makes it indifferent to its surroundings (Mestorino et al. 2013). 

Azaperone is a restricted-use drug and may be used by or on the order of a licensed veterinarian. 

Azaperone is used in veterinary medicine to reduce stress in pigs during handling and transport 

and aggression when pigs are comingled. Azaperone intramuscular doses for sedation range 

from 0.5 to 2.0 mg/kg-bw, depending on the species (IPCS 1991). WS uses all delivery methods 

to inject target animals with sedatives during WDM activities. WS uses azaperone combined with 

butorphanol tartrate and medetomidine HCl (BAMTM) and nalbuphine and medetomidine HCl 

(NAM); WS does not use azaperone independently. It should be noted that NAM does not use 

drugs regulated by the U.S. Drug Enforcement Agency, which is beneficial in many areas and has 

been shown to be effective in immobilizing black bears (Wolfe et al. 2016a). However, another 

recent study reported effectiveness, but with some concerns for the safety of personnel and 

animals, when using BAM or NAM compared to ketamine-xylazine for the immobilization of

raccoons (Johnson et al. 2023a). 
SEDATIVES 30

3.1.2 Physical and Chemical Properties

Azaperone is an odorless, white powder (University of Hertfordshire 2018c). Its molecular weight 

is 327.40 g/mol (University of Hertfordshire 2018c), with a melting point of 92°C (University of 

Hertfordshire 2018c). It is moderately water-soluble (50 mg/L at 20°C) (University of Hertfordshire 

2018c). Its log Kow is 3.3 (University of Hertfordshire 2018c), indicating it is more lipophilic than 

hydrophilic.

3.1.3 Environmental Fate

Azaperone is not expected to escape into the atmosphere, as it is nonvolatile. Azaperone is 

moderately soluble in water, and its log Kow indicates it will bind to the organic matter in soil and 

aquatic environments and be less available in solution. It strongly adsorbs to soil (Koc 304,656)

and is unlikely to leach from soil (Choi et al. 2014). The DT50 values range from 115.5–277.3 days 

for amended (added powdered blood meal as a biological fertilizer) and untreated soils (Choi et 

al. 2014). Azaperone was found in rivers on the Iberian Peninsula during an experiment that 

screened for 205 chemicals (Fàbrega et al. 2013). Bioaccumulation is unlikely because studies 

indicate azaperone excretion and metabolism is quick; tissue residues were less than 1 percent 

in male Wistar rats after 96 hours (FAO 1991).

3.1.4 Metabolism

The distribution of azaperone in rats treated with a subcutaneous injection of 1 mg/kg peaked 

within 30 minutes in blood, liver, and brain (as cited in (IPCS 1991)). Elimination of azaperone 

from the brain and blood was rapid; within 8 hours, concentration was down to 1 percent. 

Elimination from the liver was slower, down 25 percent within 8 hours. Within 24 hours, rats 

excreted 20–25% in urine, and within 48 hours excreted 60–80% in feces. No azaperone was 

detected in tissues four days after treatment (as cited in (IPCS 1991)). Azaperol is a metabolite 

of azaperone (Rauws et al. 1976). The half-life of azaperol in rats after intravenous injection was 

45 minutes for the liver and 15 minutes for the kidney and brain (Rauws et al. 1976).

3.1.5 Hazard Identification

Azaperone is moderately toxic (category III for oral toxicity). In rodents, toxic signs were ptosis 

(drooping of the upper eyelid), sedation, tremors, and clonic seizures (loss of consciousness with 

violent muscle contractions) (IPCS 1991). In one study, male rats were given doses of 5, 20, or 

80 mg/kg bw daily by gavage for 74 days (as cited in (IPCS 1991)). At the high dose, rats showed

signs of severe sedation, ptosis, and decreased food consumption and body weight throughout 

the experiment. At the 20 mg/kg bw dose, moderate sedation and ptosis occurred.

3.1.5.1 Acute Toxicity

Azaperone is moderately toxic to mammals. The acute oral LD50 for guinea pigs (Cavia porcellus), 

mice, and rats is 202 mg/kg-bw, 385 mg/kg-bw, and 245 mg/kg-bw, respectively (NCBI 2023c)

(Table 7). In a study using dogs, azaperone did not cause mortality after subcutaneous injection 
SEDATIVES 31

of 2.5 to 40 mg/kg-bw and up to 20 mg/kg-bw given orally by gavage (Pitman-Moore 1982). After 

oral administration, some dogs vomited. In another study using adult male dogs, intramuscular 

injections of 20 and 40 mg/kg-bw and intravenous injections of 10 and 20 mg/kg-bw did not cause 

mortality (Pitman-Moore 1982). Both intramuscular and intravenous injections at the low dosage 

caused muscular tremors and tranquilization. All dogs had decreased muscle reaction to painful 

stimuli, extreme muscle incoordination, and increased sweating. At the high dosages, dogs 

developed tachycardia and had increased respiratory rate and muscle spasms, causing backward 

arching of the spine, neck, and head. All symptoms subsided in all dogs 2.5 to 3 hours after 

administration. Intravenous injections of 30 and 60 mg/kg-bw and intramuscular injections of 60 

mg/kg-bw in female cats did not cause mortality (Pitman-Moore 1982). Both intravenous doses 

caused an increase in the respiratory rate, tremors/convulsions, impaired locomotion, and 

temporary bradycardia (Pitman-Moore 1982). Female cats that received the low intravenous dose 

recovered in 5-10 minutes. The 60 mg/kg-bw intramuscular dose had less effect than the 

intravenous 60 mg/kg-bw; no convulsions were observed in the cats. Azaperone administered 

intravenously had an LD50 of 42 mg/kg-bw and 25 mg/kg-bw in mice and rats, respectively (Table 

7). Azaperone is considered a skin sensitizer (NCBI 2023c).

3.1.5.2 Sublethal and Chronic Toxicity

In a subacute study, male and female rats were given azaperone orally through food over 15 

weeks (Pitman-Moore 1982). Azaperone concentrations were 10, 40, and 160 mg/100 g food,

which provided an approximate daily oral dose of 10, 40, and 160 mg/kg-bw. Food consumption 

decreased in males fed 40 and 160 mg/100 g food, and males fed a 160 mg/100 g dose had a 

decrease in body weight. Females given the high dose also had a reduction in food consumption,

and there was evidence of some changes in the female genital organs and hypophysis (pituitary). 

At the high dose, both males and females had a decrease in cholesterol, and males had an 

increase in urobilinogen. In another subacute study, male and female rats were given azaperone 

subcutaneously six days a week for 13 weeks (Pitman-Moore 1982). Doses were 2.5, 10, and 40 

mg/kg-bw. At the highest dose, males had a significant decrease in average body weight. The 

weight of the thymus in animals, given the high dose, was significantly decreased. In a subacute 

study on dogs, azaperone was given orally in gelatin capsules six days a week for three months. 

Doses were 1.25, 5, and 20 mg/kg-bw (Pitman-Moore 1982). No mortality occurred. Body weight, 

blood pressure, and heart rate were within normal range. Gross pathology and histological 

evaluation did not reveal any dose or drug-related changes. In a chronic toxicity study, male and 

female rats received diets containing 0, 10, 40, and 160 mg azaperone/100 g food, which was 

approximately 0, 10, 40, and 160 mg/kg-bw (Pitman-Moore 1982). Study durations were six, 

twelve, and eighteen months in length. Gross pathology examinations of the animals that died 

during the studies did not find evidence of drug or dose-related causes. No adverse effects were 

observed through hematology, serum analysis, urinalysis, gross pathology, and organ weights. 

At the highest dose, male and female rats had reduced food consumption and body weight gain. 

At the highest dose, females tended to develop some changes in the genital organs and pituitary. 

In a 24-month study on dogs, azaperone was orally administered in gel capsules at doses of 1.25, 

5, and 20 mg/kg-bw daily for six days per week (Pitman-Moore 1982). One dog died from causes 

unrelated to the dosing study. No chronic toxicity was detected during the dog study, which
SEDATIVES 32

measured heart rate, blood pressure, electrocardiogram, and hematological and biochemical 

parameters. A NOAEL of 630 μg/kg-bw was established based on neurobehavioral effects in dogs 

following oral administration (IPCS 1998). In one study, male rats were given doses of 5, 20, or 

80 mg/kg-bw daily by gavage for 74 days (as cited in (IPCS 1998)). No reproductive effects were 

observed for the three doses (IPCS 1998).

Azaperone tested negative in mutagenicity tests (NCBI 2023q) . A review of the evidence 

indicates azaperone is unlikely to be genotoxic, carcinogenic (IPCS 1998), teratogenic or 

embryotoxic (Pitman-Moore 1982).

3.1.6 Dose-Response Assessment

3.1.6.1 Human Health Dose Response

Azaperone is primarily used as a veterinary drug and uncommonly as an antipsychotic drug in 

humans. Information is limited on the effects of azaperone on humans. In a study, ten human 

males received 0.5 mg azaperone three times a day (3x/day; administration method not provided), 

increasing to 20 mg 3x/day (estimated 1 mg/kg-bw/day) over a 17-day period (IPCS 1991). After 

this increase, the maximum dose was given 3x/day for two months. No symptoms were observed 

up to 2 mg given 3x/day (estimated about 0.1 mg/kg bw/day). At the higher doses, sedation was 

observed. At 20 mg given 3x/day, the patient developed dizziness. No changes in hematology or 

blood chemistry were observed prior to or at the end of the 2-month treatment period. 

A pig breeder exposed to azaperone developed contact dermatitis (Brasch et al. 1991). The 

breeder regularly handled the drug for three years giving intramuscular injections of azaperone 

(0.5 mL/20 kg) behind the ear of his piglets. He did not wear gloves when handling azaperone,

and spillage on the hands regularly occurred. The photoallergy to azaperone was confirmed 

through photo patch test results and the breeder’s observation that symptoms worsened after 

sunlight exposure.

The FDA has not established a residue tolerance limit for azaperone in food products for human 

consumption. The Food and Agriculture Organization (FAO 2018) reports maximum residue limits 

in pigs of 60 μg/kg in muscle and fat and 100 μg/kg in liver and kidney. The FDA limits the use of 

azaperone to control aggressiveness when mixing or regrouping weanling or feeder pigs weighing 

up to 80 pounds to 2.2 mg/kg-bw by deep intramuscular injection (21 Code of Federal Regulations 

(CFR) 522.150). The FDA has not established an acceptable daily intake of azaperone in humans; 

the FAO (2018) reports an acceptable daily intake of 0–6 μg/kg-bw.

3.1.6.2 Ecological Dose Response

Azaperone is moderately toxic to mammals, and although it is more lipophilic, it is unlikely to 

bioaccumulate due to its short half-life. The disadvantages of azaperone are that it can cause a 

drop in blood pressure and excitation at low doses in horses (Kreeger and Arnemo 2012). Studies 

on azaperone, including acute, chronic, and subchronic toxicity studies on aquatic vertebrates 
SEDATIVES 33

and invertebrates, are limited. Male and female spiny dogfish (Squalus acanthias) were given 4 

mg/kg azaperone through the gill slit (Latas 1987). Visual observations of behavior showed that 

treated animals swam normally and did not show escape behavior immediately after treatment 

and release into a holding tank. In contrast, untreated animals had excited and agitated swimming 

behavior and showed signs of escape behavior (hitting the sides of the tank) after release. Treated 

animals accepted food after treatment whereas untreated animals did not feed for several days.

All but one of the dogfish were alive three months after the experiment; the one animal died during 

capture and sampling. 

3.2 Butorphanol

3.2.1 Chemical Description and Product Use

Butorphanol (CAS No. 42408-82-2; C21H29NO2; chemical structure in Appendix 3) and 

butorphanol tartrate (CAS No. 58786-99-5; C25H35NO8; chemical structure in Appendix 3) are

used in sedation and pain management in animals (NCBI 2023t). Butorphanol is a DEA Class IV 

controlled substance (DEA, 2018), and Federal law restricts its use by or on the order of a licensed 

veterinarian (21 CFR § 522.246). Butorphanol is an analgesic (pain relief without total loss of 

feeling or muscle movement) that acts on the central nervous system, having an affinity for opioid 

receptors. The combination of butorphanol tartrate with azaperone tartrate and medetomidine HCl 

(BAMTM) improves the quality of the anesthesia (blockage of all feeling) (see section 3.7 below).

The APHIS WS Feral Swine Program uses butorphanol in combination with medetomidine and 

midazolam. For feral dogs, WDM or WS may combine butorphanol with dexmedetomidine and 

midazolam (these other drugs are covered in this RA). In equids, the intravenous dose for 

butorphanol is 0.1 mg/kg-bw (21 CFR § 522.246 2023). Sedation doses in small mammals range 

from 0.1 to 0.4 mg/kg-bw for intramuscular injection (West et al. 2007). WS administers 

butorphanol through intravenous or intramuscular routes, whereas remote (dart) delivery is by 

intramuscular route. WS research staff have also begun using drug combinations such as 

Butorphanol, Azaperone, Medetomidine (BAM), and Medetomidine, midazolam, and butorphanol 

(MMB) for immobilizing wildlife such as feral swine.

3.2.2 Physical and Chemical Properties

Butorphanol has a melting point of 216°C and a log Kow of 3.3, indicating it is lipophilic (DrugBank 

2021b). It is moderately soluble in water (0.16 g/L) (HMDB 2019d). Its molecular weight is 327.468 

g/mol (NCBI 2023t). Butorphanol tartrate’s predicted chemical properties are a melting point of 

214°C, a logP of 4.19, and a Henry’s law of 8.37x10-10 atm-m3

/mole at 25°C (USEPA 2019b).

3.2.3 Environmental Fate

No information is currently available on the environmental fate processes and impact of 

butorphanol. It has a short half-life in animals and is excreted through urine and feces. It is 

moderately soluble in water, but its mobility in soil is unknown (the soil organic carbon-water 

partition coefficient is unavailable).
SEDATIVES 34

3.2.4 Metabolism

The onset of analgesia is a few minutes for intravenous injection of butorphanol, 10 to 15 minutes 

for intramuscular injection (Hospira 2023). The analgesic effects last about four hours (Riggs et 

al. 2008, West et al. 2007). Butorphanol is mostly metabolized in the liver (DrugBank 2021b). 

Hydroxybutorphanol is a major metabolite of butorphanol, and norbutorphanol is produced in 

smaller amounts (EMEA 1998). Butorphanol has an elimination half-life of about 18 hours, with 

elimination occurring through urine and feces (DrugBank 2021b). The half-life of butorphanol was 

approximately 71 minutes in Holstein calves given 0.025 mg/kg bw butorphanol tartrate 

administered intramuscularly (Baldridge et al. 2011). The mean serum half-life was 1.62 hours in 

adult male and female dogs administered intramuscular or subcutaneous butorphanol tartrate at 

0.25 mg/kg-bw (Pfeffer et al. 1980). One study evaluated butorphanol tartrate in two raptor 

species and found significant differences in plasma concentration-time profiles; throughout the 

study, concentrations were consistently higher in great horned owls than in red-tailed hawks 

(Riggs et al. 2008). In two of six red-tailed hawks, butorphanol concentrations in plasma after 

intravenous injection of 0.5 mg/kg-bw butorphanol tartrate into the jugular vein were undetectable 

8 to 12 hours after administration; the half-life of the elimination phase was 0.997 hours (Riggs et 

al. 2008). In great horned owls, the plasma concentration of butorphanol after intramuscular or 

intravenous injection of 0.5 mg/kg-bw butorphanol tartrate were undetectable in two of six birds 

12 to 24 hours after administration; the half-life of the elimination phase was 4.155 hours for 

intravenous injection into the jugular and 1.859 hours for intramuscular injection (Riggs et al. 

2008). 

3.2.5 Hazard Identification

The effects of a toxic dose of butorphanol are similar to those of opioid drugs . Symptoms include 

cardiovascular effects, hypoventilation, coma, and death (DrugBank 2021b).

3.2.5.1 Acute Toxicity

Butorphanol tartrate has an oral LD50 in mice of 395 mg/kg-bw, indicating it is moderately toxic

(Table 7). In humans, adverse effects felt from butorphanol toxicity include sedation, dizziness, 

nausea, clamminess, sweating, headache, vertigo, weakness, anxiety, nervousness, and 

confusion (WHO 2006).

3.2.5.2 Sublethal and Chronic Toxicity

EMEA (1998) summarizes a reproductive study where rats received 10, 40, and 160 mg/kgbw/day of butorphanol tartrate for 63 days prior to mating for males and for 14 days prior to mating 

and through the gestation period and lactation period for females. A reduction in the number of 

conceptions occurred at the 160 mg/kg-bw/day dose. From this study, butorphanol tartrate had a 

NOEL of 40 mg/kg-bw/day for embryotoxicity (EMEA 1998).
SEDATIVES 35

Butorphanol did not show evidence of carcinogenicity based on a two-year study where mice and 

rats were given butorphanol tartrate orally in the diet up to 60 mg/kg-bw/day (FDA 1998). 

Butorphanol was not genotoxic in bacteria assays (FDA 1998). 

3.2.6 Dose-Response Assessment

3.2.6.1 Human Health Dose Response

Butorphanol is an analgesic for the relief of moderate to severe pain. In people, the recommended 

dose varies depending on the patient’s age, body weight, and underlying physical conditions. The 

usual recommended dose for pain treatment is 1 mg administered intravenously, intramuscularly, 

or as a nasal spray (FDA 1998). The duration of analgesia varies depending on the pain level and 

the route of administration. Usually, it lasts 3 to 4 hours with intramuscular and intravenous doses,

with additional doses given as necessary (FDA 1998).

After receiving 20 μg/kg butorphanol intravenously, patients reported feeling dizziness, 

drowsiness, or nausea (Wetchler et al. 1989). Other toxicity symptoms observed are sweatiness, 

headache, anxiety, confusion, and lightheadedness (as cited in (WHO 2006)). In many overdose 

cases, people were not tolerant to the effects of opiates, and the initial dose was more than 2 mg 

butorphanol tartrate injection (FDA 1998). 

3.2.6.2 Ecological Dose Response

Butorphanol (0.4 mg/kg-bw) injected intramuscularly into harbor seals (Phoca vitulina) decreased 

anxiety and relaxed the animal prior to collecting biopsy samples (Tuomi 2000). The seals were 

lethargic for 1-4 hours after injection but responded to commands and ate and swam normally 

within one hour. Butorphanol caused behavioral changes in sheep in the form of restlessness, 

continual vocalization, and chewing at 0.1 and 0.2 mg/kg-bw intravenously. At 0.4 mg/kg-bw

intravenously, sheep lost control of their body movements (ataxia) (Waterman et al. 1991). In this 

study, the 0.5 mg/kg-bw dose and the 0.1 mg/kg-bw dose provided effective anesthesia to thermal 

treatments for 60 and 80 minutes, respectively. In dogs, butorphanol had an LD50 of 50 mg/kg-bw

(category II for acute toxicity) (Plumb 2018). In green iguana, butorphanol at 1.5 mg/kg-bw or 8.0 

mg/kg-bw intramuscularly gave analgesic effects in response to electrostimulation of the tail with 

no adverse side effects at the evaluated doses (Greenacre et al. 2006). Respiratory depression 

and extreme sedation in some reptile species occur at subcutaneous and intramuscular doses 

greater than 10 mg/kg-bw (Greenacre et al., 2008 in (West et al. 2007)). In avian species, 1.0-5.0 

mg/kg-bw of butorphanol given intramuscularly provides an analgesic effect (as cited in (West et 

al. 2007)). Doses of butorphanol between 25-33 mg/kg-bw subcutaneously and 0.25-0.5 mg/kgbw intramuscularly had analgesic effects on amphibians and fish, respectively (as cited in (West 

et al. 2007)). Butorphanol (0.5 mg/L) added to tank water (72-h bath) shortened the time to

consume food and normal behavior after surgery in the eastern red-spotted newt (Notophthalmus 

viridescens) (Koeller 2009).
SEDATIVES 36

3.3 Dexmedetomidine

3.3.1 Chemical Description and Product Use

Dexmedetomidine (CAS No. 113775-47-6; C13H16N2; chemical structure in Appendix 3), an 

imidazole compound, is an agonist of adrenergic alpha-2 receptors. Dexmedetomidine causes 

sedation and analgesia (Plumb 2018). Dexmedetomidine is also the active component within

medetomidine, a racemic 11 form of dexmedetomidine; however, it is approximately twice as potent 

as medetomidine (Ko et al. 2009). Dexmedetomidine and medetomidine are reviewed in separate

sections because contrasting evidence has raised questions about the common assumption of 

equipotency. The levomedetomidine in medetomidine may still play a role in drug interactions that 

would not be found in dexmedetomidine alone (Siegenthaler et al. 2020). 

Alpha-2 adrenoceptor agonist drugs have effects on both the central and peripheral nervous 

systems. Central nervous system effects include sedation, analgesia, bradycardia, respiratory 

depression, mild hypotension, and a reduction in antidiuretic hormone. Peripheral nervous system 

effects include vasoconstriction, which can lead to hypertension and a reduction in gastrointestinal 

movements (Clarke and England, 1989).

FDA approved the use of dexmedetomidine for short-term sedation and analgesia (<24 hours) of 

humans in 1999 (Kaur and Singh 2011) under the trade name Precedex® (Ko et al. 2009). 

Dexmedetomidine became commercially available for use in dogs in 2006 and cats in 2007 (FDA 

2010) under the trade name Dexdomitor® (Ko et al. 2009, Neto 2009). It can be used to provide 

chemical restraint of hyperexcitable animals (Neto 2009) during WDM activities. Dexdomitor is a 

0.5 mg/mL solution (Ko et al. 2009) available in 10 mL multi-dose vials (FDA 2010). 

WS uses dexmedetomidine to chemically restrain wildlife, including for research purposes. WS

uses the injectable formulation with all delivery devices, including remote darting or hand-syringe. 

3.3.2 Physical and Chemical Properties

Dexmedetomidine is a solid with a molecular weight of 200.285 g/mol (NCBI 2023g). 

Dexmedetomidine is freely soluble in water with a predicted solubility of 0.174 mg/mL and has a 

Log Kow of 2.8 (NCBI 2023g), indicating it is more lipophilic than hydrophilic. Dexmedetomidine 

HCl is the HCl salt form of dexmedetomidine and is used as a sedative or analgesic in animals 

(NCBI 2023g). This drug is sold under the trade name Dexdomitor, which is a white or off-white, 

crystalline, water-soluble substance with a molecular weight of 236.7 g/mol (Zoetis 2017b). 

3.3.3 Environmental Fate

The use pattern for dexmedetomidine indicates its release into the environment is unlikely. No 

data is available on this product's degradability, bioaccumulation potential, or mobility in soil

(Zoetis 2017b). As a lipophilic compound, dexmedetomidine is rapidly distributed in the body and 

readily penetrates the blood-brain barrier (EMA 2021). The protein binding of dexmedetomidine 

11 Composed of dextrorotatory and levorotatory forms of a compound in equal proportion.
SEDATIVES 37

is also high (84–95%) in mice, rats, dogs, monkeys, and humans (EMEA 2002a). In rats and dogs, 

biotransformation of dexmedetomidine occurs in the liver; metabolites are pharmacodynamically 

inactive (EMEA 2002a).

3.3.4 Metabolism

WS typically administers dexmedetomidine intramuscularly. Dexmedetomidine is lipophilic and 

subsequently well-absorbed after intramuscular administration (EMA 2021). In dogs given an 

intramuscular dose of 50 μg/kg-bw, peak plasma levels were reached after 0.6 hours. The 

elimination half-life (T1/2) is 40–50 minutes (EMA 2021). Metabolism of dexmedetomidine occurs 

in the liver in rats, dogs (EMEA 2002a), and cats (EMA 2021); metabolites lack pharmacological 

activity (EMEA 2002a); (EMA 2021). In dogs, major biotransformation pathways include 

hydroxylation, glucuronic acid conjugation, and N-methylation in the liver (EMEA 2002a); (EMA 

2021). Dexmedetomidine elimination in cats and dogs depends on hepatic (liver) blood flow and 

is excreted mainly in the urine (EMA 2021).

3.3.5 Hazard Identification

Dexmedetomidine is FDA-approved for humans and animals. As with all alpha-2 agonists, the 

potential exists for an animal administered dexmedetomidine to experience prolonged sedation, 

bradycardia, cyanosis, vomiting, apnea, or death (Drugs.com 2015). Dexmedetomidine HCl is 

considered minimally toxic for acute oral exposure (category IV), moderately toxic for singleexposure target organs (category III), and hazardous to the skin and eyes (category III) (Cayman 

Chemical 2023b). The toxicity of dexmedetomidine is high in all studied species, with sedation, 

piloerection, bulging of the eyes, salivation (rats), and convulsions (rats and dogs) are the most 

common dose-related clinical signs in mice, rats, and dogs (EMEA 2002a). In some dogs and 

cats, a decrease in respiratory rate, vomiting, or corneal opacities may also occur (EMA 2021). 

Rare instances of pulmonary edema have been reported. This drug should not be used in animals 

with cardiovascular disorders or severe systemic disease (EMA 2021). In cases of overdose in 

dogs and cats, atipamezole can be used as an antagonist (EMA 2021). Other adverse effects 

include hypotension, bradycardia, dry mouth, sinus arrest, and transient hypertension.

3.3.5.1 Acute Toxicity

In dogs, the intravenous LD50 is 2 mg/kg-bw (Table 7).

3.3.5.2 Sublethal and Chronic Toxicity

Dose-related sedation and piloerection were observed in rats and dogs during repeated dose 

studies using dexmedetomidine (EMA 2011a). Dose ranges for these studies were 20–500 μg/kgbw/day (rats, subcutaneous and intramuscular), 10–1,250 μg/kg-bw/day (rats, intravenous), and 

10-250 μg/kg-bw/day (dogs, intramuscular and intravenous). Rats also exhibited exophthalmos

(bulging of the eye), and dogs exhibited sporadic muscle twitches, irregular respiration, and 

atrioventricular block; corneal keratitis and opacity were observed in both species (EMA 2011a). 

In another 28-day repeated dose chronic toxicity study, dogs receiving daily intravenous injections 
SEDATIVES 38

of dexmedetomidine HCl had treatment-related effects, including impacts to the liver and central 

nervous system. A LOAEL of 0.01 mg/kg-bw was derived from this study (Zoetis 2017b). In 

another study, rats receiving intramuscular injections of dexmedetomidine HCl for 28 days had 

treatment-related effects associated with the eyes, adrenal gland, lungs, and the male 

reproductive system. The NOAEL in this study was 0.02 mg/kg-bw (Zoetis 2017b).

Dexmedetomidine HCl (Dexdomitor) was administered intramuscularly at ten times the 

recommended dose of 40 μg/kg-bw to 3 female and three male 7-month-old cats. Sedation 

occurred within 15 minutes of dosing and lasted a minimum of 4 hours, with full recovery occurring 

in 8−24 hours. During sedation, some cats experienced corneal dehydration and opacity, miosis, 

pale skin and gingiva, salivation, and watery ocular discharge. Vomiting occurred 7−11 hours after 

dosing in all but one animal. No mortality was observed (NLM 2014).

3.3.6 Dose-Response Assessment

3.3.6.1 Human Health Dose Response

Dexmedetomidine (dose range of 0.2 to 1.4 μg/kg-bw/hour intravenously) is used most frequently 

in humans for the sedation of adult patients in intensive care units for sedation when necessary 

(EMA 2011a). Elimination of the drug in humans is rapid, with an elimination half-life of 2.6 hours,

and occurs primarily by metabolism (EMA 2011a). However, the mean elimination half-life was 

prolonged to 3.9, 5.4, and 7.4 hours for individuals with mild, moderate, and severe hepatic 

impairment, respectively (EMA 2011a). 

Researchers in one study determined most of the radiolabeled dose of dexmedetomidine was 

recovered in urine (~94%). Unchanged parent drug was not observed in the urine, and only trace 

amounts were noted in feces (EMA 2011a). Radioactivity declined over a period of 9 days, with 

trace amounts present up to 24 days (EMA 2011a).

One study evaluating the effect of age after subjects received a 10-minute intravenous infusion 

of 0.6 μg/kg-bw dexmedetomidine indicated a higher sensitivity in young individuals. It increased 

sensitivity in females more so than males both during and immediately after infusion (EMA 

2011a). While dexmedetomidine had no effect on male or female fertility, and no teratogenic 

effects were observed in animals, the drug should not be used during pregnancy due to the 

potential effect on fetal heart rate (EMA 2011a).

Effects of dexmedetomidine on healthy volunteers include bradycardia, sinus pauses, 

hypertension, hypotension, respiratory depression, decreased heart rate, hypothermia, increased 

plasma human growth hormone, and hyperglycemia starting 0.2 to 0.7 μg/kg-bw/hour following 

intravenous administration (Keating 2015, Venn et al. 2003). Exposure may be associated with 

the accidental splashing of the drug on the skin or mucus membranes, which could result in 

sedation or hemodynamic changes (EMEA 2002a). One estimate of a worst-case scenario 

involving accidental injection of dexmedetomidine meant for an 80 kg dog suggests that profound

hemodynamic changes could occur as a result (EMEA 2002a).
SEDATIVES 39

3.3.6.2 Ecological Dose Response

Aquatic and terrestrial ecotoxicity data is limited or unavailable for dexmedetomidine. 

Dexmedetomidine may cause harm to aquatic life (Santa Cruz Biotechnology 2018); however, 

under normal use conditions, dexmedetomidine is not expected to pose a risk to the environment. 

The predicted environmental concentration surface water value for dexmedetomidine is 0.00013 

μg/L, which is below the action limit of >0.01 μg/L (EMA 2011a).

3.4 Medetomidine Hydrochloride

3.4.1 Chemical Description and Product Use

Medetomidine HCl (CAS No. 86347-15-1; C13H17CIN2; chemical structure in Appendix 3) is a high 

alpha-2 agonist receptor affinity that produces dose-dependent sedation and analgesia (NCBI 

2023i, Sinclair 2003). Alpha-2 adrenoceptor agonist drugs have central and peripheral effects. 

Medetomidine is frequently used in combination with ketamine to produce a satisfactory level of 

analgesia and muscle relaxation and can be reversed by yohimbine and atipamezole (Sinclair 

2003). WS prefers to use atipamezole as a reversal agent for medetomidine or dexmedetomidine 

(USDA APHIS 2017). This combination of drugs is frequently used in WDM for work with cervids, 

large felids, mustelids, and bears and is useful with remote dart delivery (West et al. 2007). The 

FDA approved medetomidine HCl in a 1 mg/mL concentration in the United States in 1995 under 

the trade name of Domitor® (FDA 2020). The drug is available in a concentrated form (i.e., 10, 20, 

and 40 mg/mL) with a prescription from a compounding pharmacy. WS uses medetomidine to 

sedate wildlife, often for research purposes, administering the drug intramuscularly and using 

hand or remote drug delivery methods except for oral administration.

3.4.2 Physical and Chemical Properties

Medetomidine HCl is a white or off-white, odorless, water-soluble substance with a molecular 

weight of 236.7 g/mol. Its melting point is 176–179°C (Santa Cruz Biotechnology 2019), and it is 

stable in abiotic hydrolysis and photolysis (UK Competent Authority 2014). Medetomidine is a 

lipophilic drug with a log Kow of 3.1 (DrugBank 2021f). 

3.4.3 Environmental Fate

Medetomidine HCl is considered stable in abiotic hydrolysis and photolysis studies and does not 

readily biodegrade. It also is not considered bioaccumulative (UK Competent Authority 2014). 

3.4.4 Metabolism

Medetomidine can be administered intramuscularly, intravenously, or subcutaneously. When 

given intramuscularly, medetomidine, due to its high lipid solubility, is rapidly absorbed, and peak 

plasma levels are reached within 30 minutes (as cited in (Kaartinen 2009)), with plasma protein 

binding of medetomidine at 92–95% (as cited in (Kaartinen 2009)). In cats given an intramuscular 

dose of 40 μg/kg-bw medetomidine, the peak plasma concentration is reached at approximately 

0.24 hours, and the half-life is one hour. The elimination half-life (T1/2) of 80 μg/kg-bw of 
SEDATIVES 40

medetomidine intramuscularly administered is 1.28 hours in dogs (as cited in (Kaartinen 2009)). 

Elimination occurs as a result of biotransformation in the liver (as cited in (Kaartinen 2009)). The 

primary metabolite is the N-glucuronide conjugate (UK Competent Authority 2014). When given 

intravenously, the onset of action is rapid, and the peripheral effects on the cardiovascular system 

are greater than when the drug is administered intramuscularly. The elimination half-life of 80 

μg/kg-bw of medetomidine administered intravenously is 0.97 hours (as cited in (Kaartinen 2009)). 

Subcutaneous administration results in slower and highly variable absorption times (Kaartinen 

2009).

3.4.5 Hazard Identification

As with all alpha-2 agonists, the potential exists for an animal administered medetomidine to 

experience prolonged sedation, bradycardia, cyanosis, vomiting, apnea, or death (Sinclair 2003). 

Spontaneous muscle contractions may be observed in some target animals (Sinclair 2003, Zoetis 

2021). After drug administration, blood pressure is initially increased due to peripheral 

vasoconstriction, then decreases to normal or slightly below normal levels. Respiratory responses 

include an initial slowing of respiration that returns to normal within two hours (Zoetis 2021). It has 

been noted that medetomidine should not be used in dogs with cardiac disease, respiratory 

disorders, or liver or kidney diseases. It also should not be used when dogs are stressed due to 

extreme heat, cold, or fatigue (Zoetis 2021), suggesting wildlife with these conditions could be at 

risk (these conditions would be generally unknown when tranquilizing wild animals but anticipated 

to be minimal since wild animals rarely would get supplemental veterinary care). 

3.4.5.1 Acute Toxicity

Many studies involving medetomidine were performed with medetomidine versus medetomidine 

HCl. While this risk assessment focuses primarily on studies specific to medetomidine HCl, it is 

important to note that medetomidine and medetomidine HCl can be regarded as equivalent from 

a toxicological perspective. This is due to the dissociation of HCl from medetomidine in an

aqueous environment (UK Competent Authority 2014). The LD50 in rats for medetomidine HCl is 

31 mg/kg-bw (Table 7) (UK Competent Authority 2014). In animal safety studies, dogs tolerated 

up to five times the recommended intravenous dosage of medetomidine and up to 10 times the 

recommended intramuscular dose. A single intravenous administration of 10 times the 

recommended dose in dogs caused a prolonged anesthesia-like condition with increased

spontaneous muscle contractions (Zoetis 2021).

3.4.5.2 Sublethal and Chronic Toxicity

In a 28-day repeated dose subcutaneous toxicity study, rats received 0, 0.1, 0.4, or 1.6 mg/kgbw/day of medetomidine HCl in saline. No deaths occurred; however, treatment-related effects 

included reduced body weight gain and corneal opacity of the eye. A subcutaneous LOAEL of 0.1 

mg/kg-bw/day was derived from this study (Hirsimaki, 1986a in (UK Competent Authority 2014)). 

Similarly, in a 28-day study of beagles receiving daily intramuscular injections of medetomidine 

HCl in saline of 0, 0.8, 0.24, or 0.4 mg/kg-bw/day, no deaths occurred at any dose level. No 
SEDATIVES 41

treatment-related effects were noted aside from diarrhea and corneal opacity in the mid-and highdose groups. An intramuscular NOAEL of < 0.8 mg/kg-bw/day was derived from this study 

(Hirsimaki, 1986b in (UK Competent Authority 2014)). The animal safety studies reported by 

Pfizer (Zoetis 2021) indicate that repeated doses of 3 or 5 times the recommended dose of 

medetomidine can cause profound sedation, bradycardia, reduced respiratory rates, and 

spontaneous twitching. In vitro and in vivo studies of medetomidine indicate that it is not genotoxic

(UK Competent Authority 2014). Information on the reproductive effects of medetomidine is 

limited (Zoetis 2021).

3.4.6 Dose-Response Assessment

3.4.6.1 Human Health Dose Response

Medetomidine is extensively metabolized in people and rapidly excreted. The main metabolite is 

the N-glucuronide conjugate. Medetomidine and its metabolites are distributed throughout the 

body and can cross the placenta and be excreted in breast milk (UK Competent Authority 2014). 

The drug is suspected of damaging fertility or the fetus (Cayman Chemical 2023a). Following the

intravenous injection of radioactive-labeled medetomidine in people, the maximum blood 

concentration of labeled medetomidine was reached in 10 minutes. Elimination of labeled

medetomidine from blood was rapid, with an elimination half-life of approximately 3 hours. 

Medetomidine metabolites are excreted mainly via urine. In humans, an average of 95% of 

medetomidine metabolites are excreted in the urine after 9 days, with approximately 85% 

excreted within 24 hours of drug administration. Effects of medetomidine on humans include 

hypotension, hypertension, bradycardia, reduced salivation, decreased blood pressure, 

decreased heart rate, and decreased cardiac output. Medetomidine does not appear to 

accumulate in tissues and organs (UK Competent Authority 2014). Central nervous system effects 

include sedation, analgesia, bradycardia, respiratory depression, mild hypotension, and a 

reduction in antidiuretic hormone. Peripheral nervous system effects include vasoconstriction, 

which can lead to hypertension and a reduction in gastrointestinal movements (Clarke and 

England 1989). The NOAEL for intravenous administration of medetomidine in humans is 0.4 

μg/kg bw (Abbott, 1988 in (UK Competent Authority 2014)).

3.4.6.2 Ecological Dose Response

Zebrafish (Danio rerio) have an acute 96-hour LC50 of 30 mg/L medetomidine hydrochloride, 

which is considered slightly toxic (Bätscher, 2007a in (UK Competent Authority 2014)).

Medetomidine is considered very toxic to fish in chronic exposures (UK Competent Authority 

2014). Medetomidine exposures from 0.5 to 50 nM via intraperitoneal injection or by water for a 

maximum of 54 days caused body paleness within 30 days in Atlantic salmon (Salmo salar), 

rainbow trout, Atlantic cod (Gadus morhua), and turbot (Scophthalmus maximus) (Lennquist et 

al. 2010). Exposure of fry from lumpfish (Cyclopterus lumpus) and turbot to medetomidine 

concentrations from 5–10 nM caused decreased oxygen consumption, but the effect was 

reversible (Lennquist et al. 2010). In a study involving the diatom Skeletonema costatum, the 72-

hour no observable effect concentration (NOEC) for growth rate after exposure to medetomidine 

was 0.253 mg/L, and the lowest observable effect concentration (LOEC) was 0.447 mg/L 
SEDATIVES 42

(Maunder and Vaughan, 2011 in (UK Competent Authority 2014)). This study's examination and 

other studies indicate that medetomidine is very toxic to algae (UK Competent Authority 2014).

Medetomidine, given intramuscularly at a dose of 0.01 mg/kg has analgesic and mild sedative 

effects in Pacific walrus (Odobensus rosmarus) (Moore et al. 2010). Table 7 summarizes aquatic 

toxicity values for fish and aquatic invertebrates. 

3.5 Midazolam

3.5.1 Chemical Description and Product Use

Midazolam (CAS No. 59467-70-8; C18H13CIFN3; chemical structure in Appendix 3) is a 

benzodiazepine and is commonly used in humans to sedate patients prior to procedures and treat 

generalized seizures (NCBI 2023u) and in outpatient procedures such as endoscopy and dentistry 

(Nordt and Clark 1997). Similarly, in veterinary medicine, midazolam is used to sedate animals 

prior to medical procedures (Plumb 2018). 

Midazolam is used as an anticonvulsant and muscle relaxant in wildlife immobilization (Kreeger 

and Arnemo 2012). Benzodiazepines work by inhibiting the effects of the gamma-aminobutyric 

acid (GABA) neurotransmitter (Kreeger and Arnemo 2012), which produces a calming effect, 

relaxes skeletal muscles, and induces sleep (NCBI 2023u). In animal immobilization, midazolam 

is often used in combination with dissociative agents (e.g., ketamine) during anesthesia to prevent 

convulsions that may occur from dissociative agents (West et al. 2007). Midazolam has minimal 

cardiovascular and respiratory effects (Kreeger and Arnemo 2012). It is a schedule IV-controlled 

substance. Midazolam is aqueous-based and is administered intramuscularly, intravenously, 

subcutaneously, and orally (Kreeger and Arnemo 2012). In the U.S., midazolam comes in liquid 

solutions and syrup formulations. Midazolam is revisable with flumazenil (West et al. 2007). 

WS uses midazolam to sedate animals during physical or mechanical restraint and to aid the 

induction of anesthesia with other drugs. WS uses midazolam in combination with medetomidine 

and butorphanol (MMB) in feral swine immobilization. Research has shown that MMB is 

preferable for immobilizing feral pigs due to the adequate level of immobilization and no postrecovery morbidity when compared to other drug combinations used for feral swine (Ellis et al. 

2019). The optimized ratio of a combination of these drugs is 0.06 mg/kg-bw medetomidine, 0.3 

mg/kg-bw midazolam, and 0.3 mg/kg-bw butorphanol. Medetomidine and butorphanol are 

covered elsewhere in this document. WS administers midazolam using intramuscular injection 

and remotely administers the drug when immobilizing large animals such as feral swine. 

3.5.2 Physical and Chemical Properties

Midazolam is a solid, white, to light yellow color, with a molecular weight of 325.8 (NCBI 2023u). 

It has a boiling point of 497°C and a melting point of 161–164°C (NCBI 2023u). It is moderately 

soluble in water with a solubility of 54 mg/L; the hydrochloride salt of midazolam, which is formed 

in situ, is soluble in aqueous solutions (DrugBank 2023a, NCBI 2023u). Its estimated vapor 

pressure is 5.12x10-9 mm Hg at 25°C and estimated Henry’s Law Constant is 2.80x10-11 atm-
SEDATIVES 43

m3

/mol at 25 °C (NCBI 2023u). It has a low Log Kow of 3.30 at pH 7 (EMA 2011b). It has a bitter 

taste (Nordt and Clark 1997).

3.5.3 Environmental Fate

The use pattern for midazolam indicates its release into the environment is unlikely. Information 

on its environmental fate properties is limited. Its chemical properties indicate it is moderately 

soluble in water and is non-volatile. Its Log Kow indicates it does not have the potential to 

bioaccumulate in living organisms (EMA 2011b) and would not readily bind to organic matter. 

3.5.4 Metabolism

Midazolam is metabolized in the liver (Plumb 2018) and excreted in the urine (Nordt and Clark 

1997). The duration of action is 1–2 hours (Nordt and Clark 1997), and the elimination half-life is 

about 1.5–3 hours (Nordt and Clark 1997, Plumb 2018). The metabolite alpha-hydroxy-midazolam 

has a 1-hour elimination half-life (Nordt and Clark 1997). The elimination half-life for midazolam 

is short. The intravenous dose (dose not given) elimination half-life in adults is approximately 3 

hours (mean) (DrugBank 2023a). The intramuscular administration of 10 mg midazolam had an 

elimination half-life of 4.2 hours (DrugBank 2023a). Patient recovery time following intravenous 

injection averaged 27 minutes (Nordt and Clark 1997). In people with hepatic or renal problems, 

sedation effects may last longer due to the decreased metabolism and clearance of midazolam 

(Nordt and Clark 1997).

In dogs, the midazolam half-life averages 77 minutes (Plumb 2018). In horses, the median halflife is 216 minutes after 0.05 mg/kg-bw and 408 minutes after 0.1 mg/kg-bw intravenous dose 

(Plumb 2018). 

3.5.5 Hazard Identification

Midazolam is FDA-approved for human use. Midazolam causes sleep, sedation, and amnesia in 

humans and reduces anxiety (Nordt and Clark 1997). Overdose exposure of people to 

benzodiazepines may decrease respiratory rates and cause ataxia, lethargy, slurred speech, 

sleepiness, and coma (Kreeger and Arnemo 2012). Adverse effects from midazolam are rare in 

humans; less than 5% of patients experience pain on injection, local irritation, headache, nausea, 

vomiting, and hiccups (Plumb 2018). 

In animals, residual sedation is the most common side effect post immobilization (West et al. 

2007) and potential respiratory depression (Plumb 2018).

3.5.5.1 Acute Toxicity

In rats, midazolam has an oral, intravenous, and intramuscular LD50 of 1,600 mg/kg-bw, 75 mg/kgbw, and >50 mg/kg-bw (NCBI 2023u). In mice, midazolam has an oral, intramuscular, and 

intravenous LD50 of 1,600 mg/kg-bw, >50 mg/kg-bw, and 50 mg/kg-bw, respectively (NCBI 2023u)

(Table 7).
SEDATIVES 44

3.5.5.2 Sublethal and Chronic Toxicity

Midazolam is not mutagenic, genotoxic, or carcinogenic (NCBI 2023u). Oral doses of 1, 4, or 16 

mg/kg-bw midazolam had no adverse effects on male or female fertility in rats when dosed before 

and during mating (males and females) and throughout gestation and lactation in females (NCBI 

2023u). In 13-week subchronic studies, dogs given up to 45 mg/kg-bw/day and rats given up to 

200 mg/kg-bw/day demonstrated minimum toxicity for midazolam with increased liver weight in 

rats at high doses (NCBI 2023u).

3.5.6 Dose-Response Assessment

3.5.6.1 Human Health Dose Response

The intravenous dose of midazolam in adults ranges from 0.02–0.03 mg/kg-bw and may be 

repeated at intervals to achieve sedation (Nordt and Clark 1997). In healthy adults, 1–3 mg 

midazolam given intravenously usually achieves adequate sedation for most medical procedures,

and more than 5 mg is usually not necessary (Nordt and Clark 1997). A muscular dose of 0.07–

0.08 mg/kg-bw is given for conscious sedation (Nordt and Clark 1997). In humans, the onset of 

sedation following intramuscular and intravenous injection has been reported as early as 5 

minutes, with peak effects seen within 15–20 minutes and 3 minutes, respectively (Nordt and 

Clark 1997).

3.5.6.2 Ecological Dose Response

In horses, 0.05 mg/kg-bw and 0.1 mg/kg-bw midazolam did not produce sedation; rather, it 

produced agitation and ataxia (Plumb 2018). Midazolam doses of 0.1–0.5 mg/kg-bw

intramuscularly have been used on raptors (West et al. 2007). In raptors, 1 mg/kg-bw

intramuscularly causes mild sedation and relaxation (Plumb 2018).

Canids caught in traps have been sedated with 3–4 mg/kg-bw midazolam given as tablets in food 

(West et al. 2007). Syrup formulations intended for oral administration are approved human drugs 

in the U.S. and could be prescribed for extra-label use in animals under certain circumstances. In 

wild felines, typical intramuscular and oral dosages for a tiger (Panthera tigris) are 0.08–0.14 

mg/kg-bw (15 mg/adult tiger or lion (P. leo)) (West et al. 2007). In rabbits, a dose of 0.5–2.0 mg/kgbw midazolam is given intramuscularly, subcutaneously, or intravenously for premedication and 

sedation (West et al. 2007).

Eight 1-to-3-year-old donkeys were given 0.1 mg/kg-bw midazolam intravenously to study the 

pharmacokinetics and pharmacodynamics of midazolam from the baseline time (zero) through 9-

time intervals up to 48 hours post-administration (Odette et al. 2022). There was no change in 

heart rate, respiratory rate, or head height, and no differences in tactile and auditory stimulation 

and agitation-sedation throughout the study. Rectal temperature significantly increased between 

90 and 720 minutes after administration; however, the authors think this was not a drug-related 

effect but a normal diurnal variation. Ataxia and recumbency without sedation significantly 

increased between 3 and 15 minutes after administration. Midazolam was detectable in the 
SEDATIVES 45

plasma between 3- and 30-minutes post-administration. After 45 minutes, it was detectable in the 

plasma of 5 donkeys at 45 minutes and 3 donkeys at 60 minutes. After 60 minutes, midazolam 

was not detectable in any of the donkeys.

Midazolam is commonly used in combination with other sedatives (e.g., butorphanol, 

medetomidine) and anesthetics (e.g., ketamine). In red foxes (Vulpes vulpes), the induction time 

for the combination of ketamine (30.8 mg/kg-bw)-midazolam (0.6 mg/kg-bw) was 4–6 minutes, 

with immobilization effects lasting 14–23 minutes after intramuscular injection (Kreeger et al. 

1990, West et al. 2007). The combination of midazolam (0.5 or 1 mg/kg-bw) with medetomidine 

(0.06 mg/kg-bw) has been successful in red foxes by intramuscular injection, with an induction 

time of 5–8 minutes, immobilization time of 20–25 minutes, and a recovery time of 10 minutes 

after atipamezole administration (Shilo et al. 2010). Side effects from that combination were mild 

hypertension in the foxes. Similarly, the combination of medetomidine (0.04 mg/kg-bw), 

midazolam (0.3 mg/kg-bw), and butorphanol (0.1 mg/kg-bw) was effective in sedating red fox 

(Bertelsen and Villadsen 2009). In feral swine, intramuscular injection medetomidine (0.06 mg/kgbw)-midazolam (0.30 mg/kg-bw)-butorphanol (0.30 mg/kg-bw) (MMB) provided immobilization 

within a favorable induction time (3.8 minutes for ataxia and 12.7 minutes for lateral recumbency) 

(Ellis et al. 2019). Swine did not display behavior post-immobilization that would contribute to 

morbidity. Midazolam was not detected in muscle, fat, liver, or kidney tissue in the test animals 

sampled 3-, 5-, and 7-days post-immobilization.

3.6 Nalbuphine

3.6.1 Chemical Description and Product Use

Nalbuphine (CAS No. 20594-83-6; C21H27NO4; chemical structure in Appendix 3) is a synthetic 

opioid used as pain medication (NCBI 2023p). Nalbuphine HCl is commonly sold as a prescription 

under the brand name Nubain®, which is available in two concentrations, 10 mg/mL and 20 mg/mL 

(FDA 2016). Nubain’s analgesic potency is similar to that of morphine (FDA 2016). It appears to 

function as an agonist-antagonist analgesic in the central nervous system; however, the exact 

mechanism of action is unknown (NCBI 2023p). Nalbuphine HCl is administered via a sterile 

solution injected into the veins, fat, or muscles (FDA 2016). Nalbuphine has pharmacological 

properties similar to butorphanol and produces mild analgesia and sedation with few adverse 

effects (KuKanich and Wiese, 2015 in (Wolfe et al. 2016a)). The abuse potential for nalbuphine 

is low; subsequently, this opioid is not a controlled substance under the Controlled Substances 

Act (DEA 2023). WS would use nalbuphine for wildlife immobilization, frequently in combination 

with azaperone tartrate and medetomidine HCl. WS administers the drug through hand injection 

and syringe pole as a component of NAM. WS uses a dart gun to administer the drug when 

conducting bear relocations.

3.6.2 Physical and Chemical Properties

Nalbuphine is a solid with a molecular weight of 357.45 g/mol and a melting point of 230°C as a 

hydrochloride salt (NCBI 2023p). When combined with hydrochloric acid, it forms nalbuphine HCl, 

a clear solution that can dissolve in water (35.5 mg/mL at 25°C) (DrugBank 2023c). Nalbuphine 
SEDATIVES 46

HCl has a molecular weight of 393.91 g/mol and pKa values of 8.71 and 9.96. Its log Kow is 1.4, 

indicating the drug is slightly more lipophilic than hydrophilic (HMDB 2019a). Nalbuphine HCl is 

commonly sold under the brand names Nubain and Nalpain®. Nubain is stable when stored at 

25°C and away from excessive light (Drugs.com 2023c).

3.6.3 Environmental Fate

Little information and research are available on nalbuphine's environmental fate and transport. 

The EPA predicted that the biodegradation half-life is 116 days since no experimental data is 

currently available (USEPA 2020). The environmental properties of nalbuphine HCl have not been 

thoroughly investigated; therefore, the drug's release into the environment should be avoided 

(Hospira 2019).

3.6.4 Metabolism

Nalbuphine is administered subcutaneously, intravenously, intramuscularly, or orally. Nalbuphine 

has very poor oral (enteral) bioavailability in adults and is quickly metabolized. Parenteral doses 

of 75 to 300 mg/kg-bw are used in infants and children (NIH 2018). Due to the high degree of 

conjugation in the liver at first pass, oral forms are not typically used in clinical practice (Logash 

et al. 2017). The plasma half-life of nalbuphine is 5 hours, with the duration of analgesic activity 

reported to range from 3 to 6 hours in clinical studies (DEA 2023). The maximum concentration 

is attained in 15–30 min, and it exits the body mostly through bile, although metabolites and the 

unchanged drug can be found in urine (Logash et al. 2017). Nalbuphine is expected to be 

concentrated in the blood, urine, and breast milk (HMDB 2019a, NIH 2018). However, blood and 

urine concentrations have never been quantified (HMDB 2019a). 

In a study concerning the pharmacokinetics and excretion of nalbuphine via breastmilk, seven 

nursing women received a single 20 mg dose of nalbuphine intramuscularly. Milk samples were 

collected several times, ranging from 1 to 24 hours after the initial dose. The elimination half-life 

from milk was determined to be roughly 8 hours. It was determined that an exclusively breastfed 

infant in this study would receive a dosage equivalent to 1.1% of the maternal weight-adjusted 

dosage. Because nalbuphine has poor oral absorption, it is unlikely to adversely affect breastfed 

infants (NIH 2018). According to NIH, the mean absolute bioavailability of nalbuphine is 81% and 

83% for the 10 and 20 mg intramuscular doses, respectively, and 79% and 76% following 10 and 

20 mg of subcutaneous nalbuphine (NCBI 2023p).

3.6.5 Hazard Identification

Nalbuphine is FDA-approved for human use. Nalbuphine HCl has low acute toxicity. It is ranked 

as category IV for acute oral and acute inhalation toxicity (Letco 2019). According to aggregated 

Globally Harmonized System of Classification and Labelling of Chemicals (GHS) information from 

five companies, The National Institutes of Health (NIH) has determined that nalbuphine is H302 

(100%, Harmful if swallowed), H332 (40%, Harmful if inhaled), and H336 (20%, may cause 

drowsiness or dizziness). Symptoms of nalbuphine HCl induced toxicity include irregular 
SEDATIVES 47

heartbeat and blood pressure, a variety of disorders of the central nervous system, nausea and 

vomiting, respiratory depression, and symptoms of dependence and withdrawal (Hospira 2019). 

Other adverse effects include sedation, sweaty and clammy conditions, dizziness, vertigo, dry 

mouth, and headache. Less than 1% of patients experience adverse effects in the central 

nervous, cardiovascular, gastrointestinal, respiratory, or dermatological systems or have other 

miscellaneous effects (speech, urinary urgency, blurred vision, rash, pruritus, allergic reactions).

3.6.5.1 Acute Toxicity

In dogs, the acute oral LD50 for nalbuphine is 1,100 mg/kg-bw, and intravenous LD50 is 140 mg/kgbw (Table 7). Dust or powder may irritate eye tissue (Letco 2019).

3.6.5.2 Sublethal and Chronic Toxicity

In a reproductive and fertility study, Nalbuphine HCl administered to rats subcutaneously had a 

NOAEL of 56 mg/kg-bw/day, with no effects at the maximum dose (Hospira 2019). In embryo and 

fetal development studies, nalbuphine HCl given subcutaneously had a NOAEL of 100 mg/kgbw/day in rats and 32 mg/kg-bw/day in rabbits (Hospira 2019). Fertility in male and female rats 

was unaffected by doses of Nubain up to 56 mg/kg-bw/day or 330 mg/m2

/day (Drugs.com 2023c). 

In a 24-month oral toxicity study in rats and a 19-month oral toxicity study in mice, nalbuphine HCl

had a NOAEL of 200 mg/kg-bw/day (Hospira 2019). Nalbuphine HCl is not considered 

carcinogenic (Hospira 2019). In people, chronic use of opioids can cause a deficiency in 

androgen, resulting in symptoms of infertility, impotence, amenorrhea, and erectile dysfunction 

(Hospira 2019).

3.6.6 Dose-Response Assessment

3.6.6.1 Human Health Dose Response

The maximum recommended human dose for Nubain (nalbuphine HCl) given intramuscularly, 

subcutaneously, or intravenously is 160 mg/day, or 100 mg/m2

/day for a person weighing 60 kg 

(Drugs.com 2023c). Respiratory depression occurs at the usual adult Nubian dose of 10 mg for a 

70 kg person (Drugs.com 2023c). In non-tolerant adults, the maximum single dose should be 20 

mg, with a maximum daily dose of 160 mg (Drugs.com 2023c). For inducing anesthesia, the doses 

range from 0.3 mg/kg-bw to 3 mg/kg-bw intravenous over a 10 to 15-minute period (Drugs.com 

2023c). Nubain is an opioid drug that can impair people's mental or physical abilities while under 

its influence (Drugs.com 2023c). A single subcutaneous dose of 72 mg of Nubain caused 

symptoms of sleepiness and mild dysphoria (a state of unease) in a study population of eight 

healthy adult humans (Drugs.com 2023c).

3.6.6.2 Ecological Dose Response

There is limited information on nalbuphine’s effects on wildlife. Rocky Mountain elk (Cervus

canadensis nelsoni) responded similarly at three doses of nalbuphine (0.3, 1.6, and 3.0 mg/kgbw) given by hand intramuscularly (Wolfe et al. 2014b). The elk showed transient sedation, and 

some of the animals had a diminished response to human approach. Intramuscular injection with 
SEDATIVES 48

12.5 mg/kg-bw nalbuphine in Hispaniolan parrots (Amazona ventralis), increased pedal thermal 

withdrawal thresholds up to 3 hours (analgesic effect); the higher doses of 25 mg/kg-bw and 50 

mg/kg-bw did not increase thermal thresholds (Sanchez-Migallon Guzman et al. 2011). The birds 

displayed normal behavior, and no adverse effects, including sedation, were observed. No 

nalbuphine toxicity data appears to be available for aquatic nontarget organisms.

3.7 Butorphanol Tartrate, Azaperone, and Medetomidine Hydrochloride (BAMTM)

3.7.1 Chemical Description and Product Use

The patented sedative drug mixture BAMTM [US Pat. 7795263] consists of butorphanol tartrate, 

azaperone, and medetomidine HCl. Each drug was evaluated separately in Sections 3.2, 3.1, and 

3.4, respectively. BAM provides short (5–10 minutes) induction times and quick reversal times

when using the indicated reversal agent. BAM is potent in small quantities and used for a broad 

range of species, making it practical to remotely immobilize wildlife with a dart or any hypodermic 

injection delivery method. The drug is designed so that most North American cervids can be 

darted with 2 cc’s or less. In most cases, BAM is reversed in five to ten minutes using naltrexone 

HCl and atipamezole when given intramuscularly (Harms et al. 2018, McDermott et al. 2020). WS

uses BAM to immobilize wildlife for a variety of WDM activities. BAM was not used from FY11–

FY15 but has been used since that data was analyzed.

3.7.2 Physical and Chemical Properties

BAM is commonly used as a premixed 6∶4∶3 ratio (volume/volume/volume) of butorphanol, 

azaperone, and medetomidine from respective source solutions (Wolfe et al. 2014a). The mixed 

solution is predominantly clear and contains a combination of the chemical properties of each of 

its components. BAM is sold as a a premixed solution containing 27.3 mg of butorphanol, 9.1 mg 

of azaperone, and 10.9 mg of medetomidine (Wedgewood Pharmacy 2024).

3.7.3 Environmental Fate

Limited or no information is available on the environmental fate processes and impact of BAM or 

the individual drug components. WS does not use I&E drugs frequently and at the same site, so

the risk of environmental contamination is low. 

3.7.4 Metabolism

The components of BAM are metabolized with a default withdrawal period of 30 days. The 

withdrawal period is likely shorter for white-tailed deer because laboratory analyses did not detect 

butorphanol, azaperone, medetomidine, or atipamezole in the liver or muscle of white-tailed deer 

after 11 days (W.R. Lance, unpublished data in (Wolfe et al. 2016a). In black bear, no tissue 

residues of butorphanol, azaperone, and medetomidine were detected 8 days post-injection 

(Wolfe et al. 2020). In raccoons immobilized with 0.016 mL/kg BAM (two raccoons were given an 

additional half-dose of BAM for a final dosage of 0.020 +/- 0.001 mL/kg), both butorphanol and 
SEDATIVES 49

azaperone residues were detected in homogenized muscle, fat, liver, and kidney tissue 2, 4, and 

6 days post-immobilization; medetomidine was not detected in the tissue (Johnson et al. 2023b).

3.7.5 Hazard Identification

BAM’s toxicity arises as a result of its parts. As previously described, butorphanol tartrate, 

azaperone, and medetomidine HCl are moderately toxic. Common toxic signs associated with 

high doses of the mixture include sedation, tremors, cardiovascular effects, hypoventilation, 

coma, and death. In a recent study, 27% (4/15) of the raccoons immobilized with 0.016 mL/kg 

BAM (two raccoons were given an additional half-dose of BAM for a final dosage of 0.020 +/-

0.001 mL/kg) experienced hypoxemia below 70%. Seventy-two percent (13/18) of raccoons were 

given supplemental oxygen (Johnson et al. 2023a).

3.7.5.1 Acute Toxicity

See the acute toxicity of the individual drugs in this mixture (Sections 3.1.5.2, 3.2.5.2, and 3.4.5.2). 

Table 7 summarizes acute toxicity data.

3.7.5.2 Sublethal and Chronic Toxicity

See this compound's three drugs for sublethal and chronic toxicity (Sections 3.1.5.3, 3.2.5.3, and 

3.4.5.3). 

3.7.6 Dose-Response Assessment

3.7.6.1 Human Health Dose Response

The medetomidine and butorphanol components of BAM may severely affect human respiratory 

and cardiorespiratory function (see the hazard identification section for these drugs). The adverse 

health effects from exposure to opioids such as butorphanol can be reversed with naloxone in 

humans (Kreeger and Arnemo 2012). Atipamezole will reverse the effects of medetomidine in 

animals, but it is not approved for use in humans. However, human trials have been conducted 

with atipamezole reversal of dexmedetomidine without severe side effects (Pertovaara et al. 

2005). Greenberg et al. (2018) recommend an intramuscular dose of 100 mg atipamezole for 

significant medetomidine exposure where medical aid is not available. 

3.7.6.2 Ecological Dose Response

The ecological dose response is summarized under the individual drug components (Sections 

3.1.5.2, 3.2.5.2, and 3.4.5.2). Table 7 presents information on medetomidine’s toxicity to fish and 

aquatic invertebrates. No ecological dose response data is available for butorphanol and 

atipamezole.

3.8 Nalbuphine, Azaperone, and Medetomidine (NAM)

3.8.1 Chemical Description and Product Use
SEDATIVES 50

The patented sedative drug combination NAM (or NalMed-A; US Pat. 9339498B2) consists of 

nalbuphine, azaperone, and medetomidine (Wolfe et al. 2016b). These drugs were evaluated 

separately in Sections 3.5, 3.1, and 3.4, respectively. Governmental drug enforcement agencies 

do not regulate the drugs in NAM as controlled substances, but a veterinarian prescription is 

required. 

The NAM combination uses a relatively small volumetric quantity suitable for accurate and safe 

delivery by remote dart or syringe pole (jab stick) (Wolfe et al. 2016a). The preferred relative 

weight ratio relationship of the pharmaceutically effective ingredients is 40 mg/mL of nalbuphine 

HCl, 10 mg/mL of azaperone tartrate, and 10 mg/mL of medetomidine HCl. This ratio was used 

in a study evaluating the use of NAM for raccoon immobilization (Johnson et al. 2023a). WS may

use this combination of NAM to immobilize and sedate wildlife.

3.8.2 Physical and Chemical Properties

NAM is a premixed solution in a single vial to be used in the field. See the physical and chemical 

properties above for each drug in NAM.

3.8.3 Environmental Fate

Limited or no information on the environmental fate processes and impact of BAM and NAM or 

the individual drug components is currently available. WS does not frequently use I&E drugs; 

therefore, the risk of adverse environmental impacts is low. 

3.8.4 Metabolism

The components of NAM are likely metabolized rapidly after recovery with a similar withdrawal 

time to BAM (Wolfe et al. 2016a). Nalbuphine HCl has a reportedly short elimination half-life in

dogs (Pao et al. 2000). Azaperone is metabolized by the liver and rapidly eliminated (Plumb 2018). 

Mestorino et al. (2013) reported that azaperone was not detected in pigs even when euthanized

6 hours post-injection. The Food Animal Residue Avoidance Databank recommends 8 days postinjection as a withdrawal time for azaperone (as cited in (Wolfe et al. 2018)). Cook et al. (2016)

reported that tissue residues for components of a similar immobilization combination 

(butorphanol, azaperone, and medetomidine) and the antagonists atipamezole and naltrexone 

were not detected 11 or 21 days post-injection in white-tailed deer (O. virginianus). Wolfe et al. 

(2018) reported that NAM tissue residues (0.01 mg/kg) were detected in liver and muscle tissue 

samples from elk euthanized within 40 min post-injection and one animal that died 12–24 hours

post-injection but not in tissues from any of the animals euthanized at 3, 6, 14, 21, or 28 days

post-injection. Wolfe et al. (2018) also reported that tissue residues for the antagonists naltrexone, 

atipamezole, and tolazoline were detected in the liver and muscle of the animal that died 12–24 

hours post-injection. Only naltrexone was detected in the liver from the two elk euthanized on day 

3 without antagonist residues detected thereafter. In raccoons immobilized with 0.018 mL/kg NAM

(one raccoon was given an additional half-dose of NAM for a final dosage of 0.020 +/-0.0003

mL/kg), both nalbuphine and azaperone residues were detected in homogenized muscle, fat, 
SEDATIVES 51

liver, and kidney tissue 2, 4, and 6 days post-immobilization; medetomidine was not detected in 

the tissue (Johnson et al. 2023b).

3.8.5 Hazard Identification

Nalbuphine HCl is a synthetic opioid agonist-antagonist widely used for wildlife capture as an 

analgesic and supplement to balance anesthesia. Medetomidine is a potent alpha-2 

adrenoreceptor agonist with good sedative and analgesic properties. Azaperone is a neuroleptic 

in the butyrophenone class of tranquilizers (Wolfe et al. 2018). The synergistic NAM combination 

of opioid and alpha-2 agonist drug immobilization relies more heavily on a potent alpha-2 agonist 

rather than on a potent opioid. NAM combinations have low volume and reversible effects as well 

as the benefit of greatly diminished regulatory control and greater accessibility by nonveterinary 

field personnel (Wolfe et al. 2014b).

NAM is used for reversible chemical immobilization under field conditions in a variety of species,

such as Rocky Mountain elk (Wolfe et al. 2014b) and black bears (Ursus americanus) (Wolfe et 

al. 2014b, Wolfe et al. 2016a). NAM has good quality sedation in American bison (Bison bison)

with a relatively low delivery volume (0.8 mL/100 kg containing the mean dose of 0.4 mg/kg-bw

nalbuphine, 0.08 mg/kg-bw medetomidine, and 0.08 mg/kg-bw azaperone) and rapid and smooth 

antagonism (Wolfe et al. 2017). Side effects include hypoxemia (low oxygen levels in the blood)

in American bison and raccoons (Johnson et al. 2023a, Wolfe et al. 2017) and respiratory rate 

depression in American black bears (Wolfe et al. 2016a).

Nalbuphine HCl is related to the more-potent opioids (such as etorphine HCl, carfentanil citrate, 

and thiafentanil oxalate). However, nalbuphine HCl is not regulated by the US Drug Enforcement 

Administration (DEA 2023) because the human abuse potential with nalbuphine appears to be 

quite low (Wolfe et al. 2014b).

3.8.5.1 Acute Toxicity

Table 7 gives the acute toxicity data for nalbuphine, azaperone, and medetomidine HCl and the 

sections summarizing this data under the individual drugs.

3.8.5.2 Sublethal and Chronic Toxicity 

See the sublethal and chronic toxicity sections under the individual drugs.

3.8.6 Dose-Response Assessment

3.8.6.1 Human Health Dose Response

The human health dose response for nalbuphine, azaperone, and medetomidine are discussed 

individually in this risk assessment. 

3.8.6.2 Ecological Dose Response
SEDATIVES 52

In bison (Bison bison), hand injection of a mean dosage of 0.4 mg/kg-bw nalbuphine, 0.08 mg/kgbw medetomidine, and 0.08 mg/kg-bw azaperone safely immobilized the animals (Wolfe et al. 

2017). Bison had respiratory rates within normal limits, but researchers observed hypoxemia.

Based on a study in American black bears, a recommended dose for immobilization is 0.44–0.88 

mg nalbuphine/kg-bw, 0.11-0.22 mg azaperone/kg-bw, and 0.11-0.22 mg medetomidine/kg-bw

(Wolfe et al. 2016a). As observed in other wildlife dosed with NAM, the bears had a depressed 

respiratory rate. In Rocky Mountain elk, successful immobilization was achieved at a 

concentration of 40 mg/mL nalbuphine, 10 mg/mL medetomidine, and 10 mg/mL azaperone 

dosed at 1.8–2.0 mL for darting elk (Wolfe et al. 2014b). There was a tendency towards 

hypoxemia in the elk. In raccoons immobilized with 0.018 mL/kg NAM (one raccoon was given an 

additional half-dose of NAM for a final dosage of 0.020 +/-0.0003 mL/kg), hypoxemia below 70% 

oxygen saturation was observed in 6% of study animals (Johnson et al. 2023b). See Table 7 for 

information on medetomidine’s toxicity to fish and aquatic invertebrates; information is lacking for 

nalbuphine and azaperone toxicity in aquatic species.

3.9 Xylazine

3.9.1 Chemical Description and Product Use

Xylazine (CAS No. 7361-61-7; C12H17CIN2S; chemical structure in Appendix 3) is an alpha-2 

adrenergic agonist (the sedative works primarily on the alpha-2 adrenergic receptors in the brain 

and body) inhibiting the release of norepinephrine in the central and peripheral nervous system 

(Kreeger and Arnemo 2012). Alpha-2 adrenoceptor agonist drugs have central and peripheral 

nervous system effects. Central effects include sedation, analgesia, bradycardia, respiratory 

depression, mild hypotension, and a reduction in antidiuretic hormone. Peripheral effects include 

vasoconstriction, which can lead to hypertension and reduced gastrointestinal movements 

(Clarke and England 1989). Xylazine can be purchased as Rompun®, CervizineTM, and AnaSed®. 

The drug is supplied as a sterile solution. Each mL of solution contains 20 mg xylazine, 0.9 mg 

methylparaben, 0.1 mg propylparaben, and water for injection (AnaSed® 2022). Some brands 

are available in concentrations of either 20 mg/mL (for small animals) or 100 mg/mL (for large 

animals). The drug is used as a sedative that calms nervousness, irritability, and excitement, 

usually by depressing the central nervous system. Xylazine is commonly used with ketamine to 

produce relaxed anesthesia but can also be used alone to facilitate physical restraint. The two 

most commonly used ratios are a 2:1 and a 5:1 ketamine: xylazine mixture. WS often uses a 

ketamine and xylazine combination as an alternative to Telazol (USDA APHIS 2019b).

When combined with ketamine, xylazine helps minimize muscle tension, reducing heat production 

but can lower body temperatures when working in cold conditions (Fowler and Miller 1999). 

Animals sedated with xylazine are usually responsive to stimuli; therefore, individuals handling 

these animals should minimize sight, sound, and touch (USDA APHIS 2019b). WS uses xylazine

alone to chemically restrain wildlife, such as white-tailed deer, or in combination with other 

approved program drugs. WS administers the drug using hand injection with a hand syringe or 

syringe pole and remote darting.
SEDATIVES 53

3.9.2 Physical and Chemical Properties

Xylazine is a white or almost white crystalline substance (FAO 1997). It has a molar mass of 

220.334 g/mol (NCBI 2023d) and a melting point of 165–168°C (USDA AMS 2002). It is soluble 

in methanol (50 mg/mL) but practically insoluble in water (FAO 1997, Sigma-Aldrich Corporation 

2002b, USDA AMS 2002). Xylazine is stable under normal storage conditions but is incompatible 

with strong oxidizing agents (Cayman Chemical 2022b). Xylazine is a highly lipid-soluble organic 

base (log Kow 2.8) (Le Vet BV 2017, NCBI 2023d). 

3.9.3 Environmental Fate

Information on the environmental fate of xylazine is limited in the scientific literature. In laboratory 

studies, Choi et al. (2014) found xylazine to be mobile in soils with the potential to leach. The rate 

of degradation and dissipation within artificial soil environments was slow, which may indicate an 

ability to accumulate (Choi et al. 2014, Pugajeva et al. 2017). The DT50 values ranged from 92.4–

138.6 in amended and control soils (Choi et al. 2014). Xylazine was found in rivers on the Iberian 

Peninsula (Fàbrega et al. 2013). Its detection in waters on the Peninsula may be due to the 

colocation of the manufacturer (Pugajeva et al. 2017).

3.9.4 Metabolism

Due to xylazine’s lipid-soluble organic base, it can be found in a high concentration in the kidneys, 

liver, central nervous system, and diaphragm within minutes of intravenous injection. Xylazine is 

metabolized rapidly, with approximately 70% of the metabolites eliminated in the urine and 30%

in enteric elimination (Le Vet BV 2017). The effects of xylazine diminish within 15-90 minutes after 

administration but are not completely reversed until it is fully metabolized (2–36 hours) (EMEA 

2002b) in (USDA AMS 2002).

In one study, when horses, cattle, sheep, and dogs were administered the drug intravenously, 

xylazine decreased to undetectable levels within a few hours. Metabolism of xylazine was fastest 

in sheep and dogs and slowest in horses (FAO 1997). Half-lives were the same when horses, 

cattle, sheep, and dogs received xylazine intramuscularly, and the maximum values were reached 

within 15 minutes for horses, sheep, and dogs. Pharmacokinetic parameters could not be 

determined in cattle due to low concentrations of the drug in bovine plasma (FAO 1997). The 

biological half-live for xylazine ranges from 1–58 days (as cited in (USDA AMS 2019).

3.9.5 Hazard Identification

Cattle, horses, dogs, and cats are the target species for xylazine; however, this drug is also used 

for carrying out WDM activities. Xylazine is frequently used with drugs such as ketamine to 

enhance sedative and analgesic qualities. Adverse effects from xylazine include respiratory 

depression, bradycardia, hypotension, reversible arrhythmia, dry mouth, and hyperglycemia, with 

considerable variation of effects among species. Thermoregulation also can be impacted (Le Vet 

BV 2017). Xylazine has caused premature parturition in cats and cattle (Le Vet BV 2017). 
SEDATIVES 54

Because xylazine affects the central nervous system, it can produce complications such as bloat. 

Bloat occurs most frequently in ruminants and can be fatal (USDA APHIS 2019b).

Strongly sedated animals are drowsy and will walk with an uncoordinated gait, which can lead to 

injury or death if physical hazards such as steep ledges or water are nearby. Sedated animals 

are also more susceptible to predators. Xylazine usually makes an animal’s breathing slower and 

shallower, which can be a concern if an animal has increased oxygen demands from being 

captured (USDA APHIS 2019b).

Cardiac arrhythmia, hypotension, seizures, central nervous system, and respiratory depression 

may occur in the event of an accidental overdose of xylazine (Le Vet BV 2017). If breathing is too 

shallow or slow, xylazine can be antagonized by alpha-2 adrenergic antagonists such as 

yohimbine or tolazoline (Le Vet BV 2017, USDA APHIS 2019b).

The SDS indicates xylazine hydrochloride is a skin and eye irritant and can cause serious eye 

damage (Sigma-Aldrich Corporation 2023); however, xylazine is not a skin or eye irritant (SigmaAldrich Corporation 2022).

3.9.5.1 Acute Toxicity

Acute oral toxicity of xylazine in rats (Table 7) was determined to be moderately toxic (IPCS 2015). 

In one study involving adult dogs and cats receiving intramuscular or intravenous administration 

of xylazine at 10 times the recommended therapeutic dose, one cat out of three receiving the 

intravenous dose died, and two dogs out of four receiving the intramuscular dose died. The 

remaining animals experienced convulsions, unconsciousness, and respiratory depression but 

recovered with no apparent long-term effects. The authors of this study concluded that xylazine 

was slightly toxic (as cited in (IPCS 2015)).

3.9.5.2 Sublethal and Chronic Toxicity

One study concluded that beagles receiving oral administration dosages of 0, 10, 30, or 100 mg 

xylazine (0, 0.3, 0.9, or 3 mg/kg-bw) for 13 weeks had no treatment-related adverse effects (as 

cited in (IPCS 2015)). However, xylazine concentration in the feed was not analyzed for 

confirmation of content, homogeneity, and stability. The Joint FAO/WHO Expert Committee on 

Food Additives has retained a NOEL of 3 mg/kg-bw from this study (EMEA 2002b). 

In a study on embryotoxicity/teratogenicity that does meet scientific standards, pregnant rats 

receiving xylazine (0, 1, 4, or 16 mg/kg-bw per day) showed treatment-related maternal effects,

including underactivity, ataxia, and slightly reduced body weight gain in the high dose (16 mg/kg 

bw) group only. Subsequently, the NOAEL in this study was 4 mg/kg-bw. No teratogenic effects 

were observed (as cited in (IPCS 2015)). Xylidine, a metabolite of xylazine, may be carcinogenic 

to humans as a result of multiple-dose studies in animals (IARC 1993).
SEDATIVES 55

Studies on neurotoxic effects were not identified in the literature. Endocrine effects have been 

observed in livestock (Greene and Thurmon 1988); however, xylazine is not on the USEPA 

endocrine disruptor list for humans.

3.9.6 Dose-Response Assessment

3.9.6.1 Human Health Dose Response

Xylazine is not approved for use in humans but has recently come under DEA concern regarding 

an increasingly recognized potential for abuse. Accidental or intentional ingestion or injection of 

xylazine by humans is hazardous (Hoffmann et al. 2001). It includes symptoms such as central 

nervous system depression, respiratory depression, hypo- and hypertension, bradycardia, 

tachycardia, ventricular arrhythmias, and transient hyperglycemia. Inhalation of xylazine can 

cause similar symptoms (Yong-Fu et al. 2013). The lowest published toxic dose of xylazine in 

humans is 14 mg/kg-bw (intramuscular) (NCBI 2023d). Oral doses of 170 μg/kg-bw have been 

reported to produce initial pharmacological effects, while acute toxic effects start at 700 μg/kg-bw

(EMEA 2002b). Fatal doses recorded have been as low as 40 mg, while some individuals have 

survived exposures above 2,400 mg (Ruiz-Colón et al. 2014). A case report described one nearly 

fatal human suicidal overdose through drinking 4 mL of xylazine (Gallanosa 1981). Accidental 

fatal overdoses associated with xylazine have occurred (Reyes et al. 2012). The use of xylazine 

in illicit street drugs, including fentanyl, cocaine, and heroin, has increased in the United States in 

recent years leading to an increased prevalence of xylazine in fatal opioid overdoses (Alexander 

et al. 2022).

3.9.6.2 Ecological Dose Response

Dose and effect information for vertebrate terrestrial nontarget organisms is limited to studies on 

domestic animals (see Hazard Identification section). Xylazine’s effects are of short duration, 

which is preferred particularly in field anesthesia or sedation when rapid recovery is needed (West 

et al. 2007). 

Information on aquatic effects from xylazine exposure is limited. In one study using the freshwater 

cladoceran, Daphnia magna, the acute 48-hour median effective concentration (EC50) was >18 

mg/L (University of Hertfordshire 2018a). A 20 mg/kg dose of xylazine injected into the 

hemolymph of blue crabs (Callinectes sapidus) gave short-term (under 10 minutes) light 

anesthesia (Quesada et al. 2011). The criteria for light anesthesia were a loss of righting reflex 

and defensive response, slow and occasional limb movement, and slow limb withdrawal when 

pressed with forceps. Bradycardia was an observed significant side effect, but the crab’s heart 

rate approached baseline within 10 minutes. Xylazine is not recommended for use in salmonids 

based on a study where the lowest effective dose (100 mg/kg-bw) produced apnea during 

induction and recovery and caused convulsion activity in brown and rainbow trout (Oswald 1978).
TRANQUILIZERS 56

4 TRANQUILIZERS

WS uses tranquilizers to calm an animal and reduce fear or sensitivity to stress. They are used 

with anesthetic, narcotic, or sedative drugs to offset side effects and facilitate the transport and 

holding of wild animals (Kock et al. 2012). 

Animals that need to be relocated or released may need to be chemically immobilized for safe 

handling. Immobilizing drugs such as ketamine, xylazine, and Telazol have been used safely on 

animals tranquilized with acepromazine and propionylpromazine hydrochloride (PPZH). APHIS 

no longer uses PPZH; thus, PPZH is not covered in this assessment. The use of tranquilizer drugs 

by WS employees is restricted to individuals who have completed specific training requirements 

(USDA APHIS 2019a).

4.1 Acepromazine

4.1.1 Chemical Description and Product Use

Acepromazine (CAS No. 61-00-7; C19H22N2OS; chemical structure in Appendix 3), a 

phenothiazine derivative, is a tranquilizer that acts as a dopamine receptor antagonist in the 

central nervous system, causing sedation, muscle relaxation, and reduction in spontaneous 

activity. This drug was first used as an antipsychotic agent in humans but is now most frequently 

used as a sedative to calm anxious animals (NCBI 2023n). Acepromazine maleate is used in 

veterinary medicine to tranquilize dogs, cats, and horses (Forney 2013). The drug is also 

occasionally used to calm trapped canids (West et al. 2007). By itself, acepromazine is not an 

effective immobilizing agent (West et al. 2007), but the combination of acepromazine maleate and 

medetomidine HCl is safe and effective for use on wildlife species (Wolfe et al. 2014a). WS

combines acepromazine with other drugs, such as BAM and NAM, to immobilize wildlife species.

Field applications are through hand injection or with a syringe pole.

4.1.2 Physical and Chemical Properties

Acepromazine is used in combination with benzyl alcohol to create an injectable solution (Bayer 

Healthcare 2014). Its molecular weight is 326.46 g/mol (NCBI 2023n). The solution is yellow and 

odorless with a density of 0.99 g/cm3 at 20°C and is water soluble with a predicted solubility of 

0.0098 mg/mL (Bayer Healthcare 2014, DrugBank 2021c). Its flash point is >93.0°C, and its 

boiling point is 110°C. The predicted log Kow for acepromazine is 4.32 and 3.49, indicating the 

drug is lipophilic (HMDB 2019e). This solution is stable under normal conditions (Boehringer 

Ingelheim 2019).

4.1.3 Environmental Fate

Information on acepromazine’s environmental fate is limited in the scientific literature. In 

laboratory studies, acepromazine strongly adsorbs to soil (Koc 52,138) but quickly dissipates or 

degrades, with DT50 values of 4.1–7.0 days in untreated and amended soils (Choi et al. 2014).
TRANQUILIZERS 57

The preferential binding of acepromazine to soil suggests it is unlikely to leach or runoff and 

impact surface or groundwater (Choi et al. 2014).

4.1.4 Metabolism

Acepromazine may be administered subcutaneously, intravenously, orally (Bayer Healthcare 

2015), or intramuscularly (Forney 2013). The effects of this drug will last from 1 to 4 hours and 

depend upon the dosage and species. Acepromazine is metabolized by the liver and excreted in 

the urine (Forney 2013). A major metabolite observed in humans is 2-(1-hydroxyethyl)promazine 

(Elliott and Hale 1999), and a major metabolite observed in the urine and plasma of horses is 

hydroxyethylpromazine sulphoxide (Wieder et al. 2012). In horses, the metabolism rates appear 

to depend upon the route of administration. In a recent study assessing intravenous administration 

of acepromazine, the drug was detectable in plasma for 3 hours but barely detectable in urine at 

any point, indicating rapid metabolism. The greatest conversion of acepromazine occurred in the 

first 10 minutes following intravenous administration (Schneiders et al. 2012). In contrast, Chou 

et al. (1998) reported that acepromazine could be detected for up to 48 hours in serum after 

intramuscular administration. The elimination half-life of 30 mg acepromazine intravenously 

administered to horses was 2.0 ± 0.5 hours (Schneiders et al. 2012). In another study, horses 

intravenously injected with acepromazine demonstrated an elimination half-life of approximately 

3 hours (Ballard et al. 1982). 

4.1.5 Hazard Identification

Acepromazine, combined with other drugs, has been used in various wildlife species but is 

routinely used in dogs, cats, and horses. It acts rapidly in dosed animals with a low order of toxicity 

(Bayer Healthcare 2015). Side effects include hypotension due to decreased vasomotor tone, 

respiratory rates, thermoregulatory abilities, and bradycardia. Acepromazine also causes a dosedependent decrease in hematocrit in dogs and horses (Forney 2013). In horses, acepromazine 

can cause penile prolapse at doses of 0.01 mg/kg-bw and higher (Ballard et al. 1982). 

Phenothiazines such as acepromazine may increase the toxicity of organophosphates (Bayer 

Healthcare 2015). Acepromazine should not be used in animals that are pregnant, dehydrated, 

anemic, or in shock, or have liver disease, heart disease, epilepsy, injury, or debilitation. An 

overdose of acepromazine results in excessive sedation, slowed respiration and heart rate, pale 

gums, unsteady gait, poor coordination, or an inability to stand. In some cases, unconsciousness, 

seizures, and death may occur (Forney 2013).

Acepromazine decreases an animal’s ability to thermoregulate; thus, temperature extremes and 

inclement weather conditions are hazardous to tranquilized animals. Acepromazine should not be 

used in high ambient temperatures (West et al. 2007).

4.1.5.1 Acute Toxicity

In animal toxicity studies, acepromazine has a low-order acute toxicity with an oral LD50 of 256.8 

mg/kg-bw in laboratory house mice and 400 mg/kg-bw in laboratory rats (Bayer Healthcare 2015).

The intravenous LD50 in mice and rats was 65 mg/kg-bw and 95 mg/kg-bw (Table 8).
TRANQUILIZERS 58

Table 8. Acute toxicity values for acepromazine and its components.

Chemical Test Species Test Type LD50 Reference

Acepromazine 

maleate

House Mouse* Acute oral 256.8 mg/kg-bw (Bayer Healthcare 2015)

Acepromazine 

maleate

Brown Rat* Acute oral 400 mg/kg-bw (Santa Cruz Biotechnology 

2007)

Acepromazine 

maleate

Brown Rat* Intravenous 95 mg/kg-bw (Santa Cruz Biotechnology 

2007)

Acepromazine 

maleate

House Mouse* Intravenous 65 mg/kg-bw (Santa Cruz Biotechnology 

2007)

Benzyl Alcohol 

(component) 

Brown Rat* Acute oral 1230–3100 mg/kg-bw (Bayer Healthcare 2014)

* Domestic laboratory strains.

4.1.5.2 Sublethal and Chronic Toxicity

In animal studies, acepromazine shows low-order chronic toxicity (Bayer Healthcare 2015). 

Chronic toxicity tests of acepromazine maleate in rats indicated no deleterious effects on renal or 

hepatic function or hemopoietic activity (Bayer Healthcare 2015). No adverse effects were 

observed in a study where beagles were treated for six months with daily doses of 20 to 40 mg/kgbw (Bayer Healthcare 2015). In another study, with increasing doses of acepromazine maleate 

up to a level of 220 mg/kg-bw daily, beagles showed some signs of pulmonary edema and 

hyperemia of internal organs, but no animals died (Bayer Healthcare 2015). 

4.1.6 Dose-Response Assessment

4.1.6.1 Human Health Dose Response

Acepromazine was halted for human use in the 1950s due to side effects and a lack of efficacy

(Collard and Maggs 1958). As a result, acepromazine is now used exclusively in veterinary 

medicine, and human toxicokinetic data is limited. Bayer (2014) reports that acute oral toxicity of 

acepromazine maleate in humans has a lowest dose that will cause death (LDLo) of 496 mg/kg, 

while Algren and Ashworth (2015) discuss in more detail the toxicokinetic data associated with an 

intentional acepromazine overdose. Following the ingestion of 950 mg of acepromazine, an adult 

woman experienced increased drowsiness, tachycardia, and hypotension. Her 1-hour postingestion plasma acepromazine level was 63 ng/mL, which decreased to 8.9 ng/mL 8 hours postingestion. The elimination half-life was 2.95 hours. Central nervous system and respiratory 

depression resolved within 8 hours of exposure, which is similar to previous case studies (Algren 

and Ashworth 2015). 

4.1.6.2 Ecological Dose Response

Ecological dose response data for acepromazine and terrestrial nontarget vertebrates is limited 

to the previously discussed studies using laboratory and domestic animals. 
ACCESSORY DRUGS 59

No effects data appear to be available testing the toxicity of acepromazine to fish and aquatic 

invertebrates. During a 72-hour test, the benzyl alcohol component of acepromazine maleate 

resulted in a median inhibition concentration (IC50) greater than 100 mg/L for algae (Bayer 

Healthcare 2014). During a 0.5-hour test, exposure to the benzyl alcohol component of 

acepromazine maleate on Photobacterium phosphoreum, a bioluminescent bacterium, resulted 

in an EC50 of 71.4 mg/L (Bayer Healthcare 2014). 

5 ACCESSORY DRUGS

All of the accessory drugs, except over-the-counter antibiotics (Appendix 1), that WS uses are to 

reduce side effects from sedatives or reverse sedation. Alpha-2 antagonist drugs displace alpha2 agonist sedatives from receptor sites in the brain, reversing sedation effects (Kock et al. 2012). 

These drugs are used to speed recovery and are most effective if administered intravenously. 

They can be injected into the muscle but metabolize more slowly (USDA APHIS 2019b). 

The toxicity of accessory drugs to the target species, people, and nontarget species is a primary 

concern. Table 9 gives toxicity values for most accessory drugs and substances (for atropine, see

Table 12). These are discussed in the following sections for each drug. Toxicity data were

available for the atipamezole, doxapram HCl, tolazoline HCl, and yohimbine. 

 

Table 9. Acute toxicity values for immobilization recovery drugs.

Chemical1 Test Species Test Type LD50 Test Result Reference

Atipamezole Brown Rat* Subcutaneous 44 mg/kg-bw (Bahri 2008, Zoetis 2017d)

Doxapram HCl Brown Rat* Acute oral 261 mg/kg-bw (Boehringer Ingelheim 2018)

Doxapram HCl House Mouse* Acute oral 270 mg/kg-bw (EMEA 1999)

Doxapram HCl Dog Acute oral 150 mg/kg-bw (EMEA 1999)

Doxapram HCl House Mouse* Intravenous 75 mg/kg-bw (Ward et al. 1968)

Tolazoline HCl Brown Rat* Acute oral 1200 mg/kg-bw (Akorn Animal Health 

2015;2018a)

Tolazoline HCl House Mouse* Acute oral 400 mg/kg-bw (Akorn Animal Health 2018a)

Tolazoline House Mouse* Intraperitoneal 160 mg/kg-bw (NCBI 2023e)

Tolazoline House Mouse* Intravenous 40 mg/kg-bw (NCBI 2023e)

Naltrexone House Mouse* Acute oral 1100-1500

mg/kg-bw

(NCBI 2023y)

Naltrexone Brown Rat* Acute oral 1450 mg/kg-bw (NCBI 2023y)

Naltrexone Guinea Pig Acute oral 1490 mg/kg-bw (NCBI 2023y)

Naltrexone House Mouse* Subcutaneous 551 mg/kg-bw (American Society of HealthSystem Pharmacists 2017)

Naltrexone House Mouse* Intravenous 180 mg/kg-bw (American Society of HealthSystem Pharmacists 2017)

Yohimbine HCl House Mouse* Acute oral 43 mg/kg-bw As cited in (IPCS 1992)

Yohimbine HCl House Mouse* Subcutaneous 20 mg/kg-bw (IPCS 1992)

Yohimbine HCl Brown Rat* Intraperitoneal 55 mg/kg-bw (Cayman Chemical 2020)

Yohimbine HCl House Mouse* Intraperitoneal 45 mg/kg-bw (Cayman Chemical 2020)

* Domestic laboratory strains.

1Atropine acute toxicity values can be found in Table 12.
ACCESSORY DRUGS 60

5.1 Atipamezole 

5.1.1 Chemical Description and Product Use

Atipamezole HCl (CAS No. 104075-48-1; C14H17CIN2; chemical structure in Appendix 3) has a 

high affinity for alpha-2 receptors in humans and rodents (Bahri 2008). Atipamezole is approved 

by the FDA to reverse the sedative and analgesic effects of medetomidine HCl and 

dexmedetomidine HCl in dogs (Bahri 2008) but is also commonly used in other species (West et 

al. 2007). It is 200−300 times more selective for the alpha-2 receptor than yohimbine, which 

provides a more rapid reversal of anesthesia. Atipamezole was developed in conjunction with 

medetomidine (alpha-2 agonist) and, more recently, dexmedetomidine, but it is also administered 

to reverse the effects of xylazine (University of Colorado 2012). In the United States, atipamezole 

is sold under the trade name Antisedan®. Each mL of the drug contains 5.0 mg atipamezole HCl, 

1.0 mg methylparaben, 8.5 mg sodium chloride, and water for injection (Antisedan® 2012). WS

intends to administer atipamezole HCl intravenously or intramuscularly by hand with a syringe 

needle to reverse the effect of sedation by medetomidine, dexmedetomidine, and xylazine in 

wildlife (USDA APHIS 2019b). Atipamezole works more efficiently through intravenous injection 

but can be injected intramuscularly, although it will take longer to take effect (USDA APHIS 

2019b). 

5.1.2 Physical and Chemical Properties

Atipamezole is a crystalline solid with a 248.75 g/mol molecular weight. Atipamezole is soluble in 

organic solvents such as ethanol, dimethyl sulfoxide, and dimethyl formamide. It is stable under 

normal storage conditions (Cayman Chemical 2022a). Its predicted log Kow is 3.32 and 2.95 

(HMDB 2019b). 

5.1.3 Environmental Fate

Information concerning the environmental fate of atipamezole in the scientific literature is limited.

The environmental fate of atipamezole under WS use is undetermined.

5.1.4 Metabolism

Atipamezole is rapidly absorbed following intramuscular injection. The onset of arousal usually 

occurs within 5 to 10 minutes after injection in most species, depending on the depth and duration 

of sedation (Jalanka and Roeken 1990, Vähä-Vahe 1990, Zoetis 2020). The elimination half-life 

is 1.3 hours in rats (Bahri 2008) and approximately 3 hours in dogs (Bahri 2008, Zoetis 2020). In 

raccoons, residues of atipamezole were detected in homogenized muscle, fat, liver, and kidney 

tissue 2, 4, and 6 days post-administration of a concentration of 5.0 mg atipamezole per 1.0 mg 

medetomidine. Atipamezole undergoes extensive hepatic biotransformation, and metabolites are 

excreted primarily in the urine (Bahri 2008, Zoetis 2020). 
ACCESSORY DRUGS 61

5.1.5 Hazard Identification

Atipamezole is a weak lipophilic base. When intramuscular administration occurs, absorption is 

rapid (Bahri 2008). Atipamezole displaces alpha-2 adrenergic agonist drugs and rapidly blocks or 

reverses sedative and analgesic drug effects (Bahri 2008). In dexmedetomidine-treated dogs, 

57% could stand after 5 minutes, and 96% stood after 15 minutes. Dogs treated with 

medetomidine had similar responses (Zoetis 2020). In medetomidine-treated cats, the median 

arousal time was 5 minutes, and the walking time was 10 minutes (Vähä-Vahe 1990). 

Atipamezole is highly selective, minimizing undesirable effects (Bahri 2008). Atipamezole is welltolerated in healthy dogs receiving doses 10 times the recommended dose or repeated doses at 

one, three, and five times the recommended dose (Zoetis 2020). Atipamezole is not considered 

a carcinogen (Zoetis 2017d).

5.1.5.1 Acute Toxicity

Acute toxicity data is limited for atipamezole. The subcutaneous LD50 in rats is 44 mg/kg-bw (Table 

9). Atipamezole is well-tolerated in healthy dogs receiving 10 times the recommended dose or 

repeated doses at one, three, and five times the recommended dose (Zoetis 2020). 

5.1.5.2 Sublethal and Chronic Toxicity

Information on the sublethal and chronic effects of atipamezole is limited. The finding that dogs 

tolerated receiving 10 times the recommended dose of atipamezole suggests minimal chronic 

toxicity potential (Pfizer 2016).

5.1.6 Dose-Response Assessment

5.1.6.1 Human Health Dose Response

Atipamezole has a wide safety margin in humans, with doses up to 100 mg administered 

intravenously without adverse effects (Jalanka and Roeken 1990, Pertovaara et al. 2005). The 

elimination half-life in humans receiving atipamezole intravenously is 1.7−2.0 hours. 

Cardiovascular or subjective side effects were not reported at doses up to 30 mg (Pertovaara et 

al. 2005). Motor restlessness, increased blood pressure and salivation, sweating, shivering, and 

cold hands were reported after a dose of 100 mg, but not with smaller doses. The highest 

atipamezole dose (100 mg) also increased systolic and diastolic blood pressure and plasma 

norepinephrine concentration, while lower doses had no significant effects (Karhuvaara et al. 

1990).

5.1.6.2 Ecological Dose Response

We were unable to find information to evaluate the ecological dose response. Atipamezole is not 

classified as environmentally hazardous (Zoetis 2017d).
ACCESSORY DRUGS 62

5.2 Atropine

5.2.1 Chemical Description and Product Use

Atropine (CAS No. 51-55-8; C17H23NO3; chemical structure in Appendix 3) is an alkaloid produced 

by several plant families, including plants in the Solanaceae family. Atropine is manufactured 

usually by extraction from solanaceous plants, deadly nightshade (Atropa belladonna), 

Jimsonweed (Datura stramonium), and corkwood (Duboisia myoporoides) or through synthetic 

processes (IPCS 2002). 

Atropine is an anticholinergic agent that blocks the neurotransmitter acetylcholine in the nervous 

system. In veterinary medicine, atropine sulfate (anhydrous, CAS No. 55-48-1; C34H48N2O10S; 

chemical structure in Appendix 3) is given to reduce salivary and airway secretions during general 

anesthesia (NCBI 2023r). For example, ketamine HCl is an anesthetic agent commonly used on 

wild carnivores (Acosta-Jamett et al. 2010), but side effects include excessive salivation, among 

other effects (Riviere and Papich 2017). In animals, dosages of atropine sulfate are mostly within 

the range of 0.01 mg/kg to 0.05 mg/kg (West et al. 2007). In several avian species, 0.01–0.02 

mg/kg-bw atropine sulfate may be given as a pre-anesthetic intramuscularly or intravenously. In 

pigs and rabbits, 0.04 mg/kg-bw is used, and 0.05 mg/kg-bw is used in laboratory rats, mice, 

gerbils (Meriones unguiculatus) and hamsters (Mesocricetus auratus) (West et al. 2007). Table 

10 summarizes recommended atropine sulfate dosages in several animals. WS would use 

atropine sulfate as an intramuscular injection by hand syringe and needle to reduce salivation and 

airway secretions and increase the heart rate in xylazine-immobilized animals. 

 

Table 10. Recommended atropine sulfate dosages for animals. 

Animal Dose

(mg/kg-bw)

Injection Type Notes

Crocodiles, alligators, most avian spp. 0.01-0.02 Intramuscular

Most avian species 0.01-0.02 Intravenous

Bear 0.02 Intramuscular

Otter 0.02 Intramuscular

Domestic ferret 0.02-0.05 may be given as a 

premedication to maintain the 

heart rate and decrease 

secretions

Common Ostrich (Struthio camelus) 0.035

Pig 0.04 Intramuscular

Rabbit, viverrids, procyonids 0.04 Intramuscular

Avian species 0.04-0.1 Intramuscular, 

intravenous

bradycardia

Rat, mouse, gerbil, hamster 0.05 Intramuscular In rabbits, 0.2-2.0 mg/kg briefly 

caused moderate tachycardia

Reference: (West et al. 2007)

5.2.2 Physical and Chemical Properties

Atropine is a colorless or white crystalline powder and odorless with a molecular weight of 289.4 

g/mol (NCBI 2023r). It has a melting point of 118.5°C (NCBI 2023r). Atropine is not volatile, with 
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a low vapor pressure of 2.59x10-3 mPa at 20°C (University of Hertfordshire 2018b) and a Henry’s 

Law Constant of 2.73x10-13 atm-m3

/mole at 25°C (NCBI 2023r). The pH of atropine is alkaline 

(NCBI 2023r). Atropine has a log Kow of 1.83 at 25°C (relatively low lipophilicity) (NCBI 2023r). 

Atropine is available in 0.5 and 2.0 mg/mL concentrations (USDA APHIS 2019b).

Atropine sulfate anhydrous is a colorless crystal or white crystalline powder that is odorless and 

very bitter (IPCS 2002) with a molecular weight of 676.83 g/mol. It has a melting point of 190 to 

194°C (IPCS 2002). Atropine sulfate has the same vapor pressure, Henry’s Law Constant, and 

log Kow as atropine (NCBI 2023r).

5.2.3 Environmental Fate

Literature on the fate of atropine and atropine sulfate in the air, soil, and water is limited. Atropine 

is nonvolatile, indicating movement into the air during administration or through respiration from 

a treated animal is not a pathway. Atropine is soluble in water. Although atropine is photosensitive,

atropine sulfate is slowly degraded by light (NCBI 2023r). The log Kow and pKa values for atropine 

suggest it would be mobile in plant xylem (Jandrić et al. 2013). Some evidence of atropine uptake 

in plants and binding to soil has been found. In a greenhouse study, researchers measured the 

uptake of atropine and its transformation products in soil by wheat (Jandrić et al. 2013). They 

applied 0.1 mg/kg 14C-atropine or 0.2 mg/kg 14C-atropine to soil. Fifteen days after planting, roots 

and leaves had measurable amounts of atropine or its transformation products. Atropine (labeled 

and unlabeled) was detected in the leaves, stems, roots, and seeds, with the highest percentage 

detected in the leaves and the lowest in the seeds, likely due to the amounts of water moving into 

the leaves through transpiration (Jandrić et al. 2013). In the same paper, researchers reported 

atropine in soil leachate 30 days after planting, but the amount decreased after 60 days, likely 

due to atropine binding to soil (Jandrić et al. 2013). They further measured the amount of 14Catropine and transformation products bound to soil 30 days after planting and determined 60 

percent was bound to soil (Jandrić et al. 2013). Bacteria, including strains of Corynebacterium

and Pseudomonas commonly found in nature, can break down atropine in as little as 48 hours of 

incubation at 30°C (Kedzia et al. 1961). Several bacterial species contain esterase, which breaks 

down atropine into tropinol and tropic acid (Jandrić et al. 2013).

5.2.4 Metabolism

In the human body, hepatic metabolism eliminates approximately half of a dose of atropine, with 

the remainder of atropine and atropine sulfate excreted unchanged in the urine (Kalser 1971, Van 

Der Meer et al. 1986). After an intramuscular injection of 2 mg of 2,4-

14C-atropine into one male, 

77–94% of the dose was excreted in urine within 24 hours, and at least one-third remained 

unchanged (Kalser 1971). In another paper, the percent of atropine excreted in parent form was 

relatively high (the range of 44–69%) (Jjemba 2006). One human male (weight and age not given),

when given a dose of 2 mg of atropine sulfate and 100 uCi [3

H]-atropine sulfate, excreted in his 

urine noratropine, atropine-N-oxide, tropine, and tropic acid, all metabolites of atropine, with 50%

of the dose excreted unchanged (Van Der Meer et al. 1986). Atropine half-life is approximately 4 

hours (NCBI 2023r).
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Intraperitoneal injection of 3

H-atropine into rats at doses ranging between 1.5 mg/kg-bw and 10 

mg/kg-bw resulted in half-lives of 40 to 46 minutes in plasma, 52 to 56 minutes in the heart, 50 to 

58 minutes in the kidney, 71 to 82 minutes in the brain, and 97 to 106 minutes in fat tissue 

(Harrison et al. 1974). 

5.2.5 Hazard Identification

Atropine and atropine sulfate interacts with the nervous system, competing with acetylcholine for 

binding sites on the muscarinic receptors. Atropine and atropine sulfate is used to resolve 

neurotoxicity from organophosphate insecticides and other toxic nerve agents. However, atropine 

toxicity can cause nervous system effects such as hyperactivity, hallucinations, and 

hypersensitivity (IPCS 2002). Toxic amounts of atropine can cause drowsiness, stupor, 

convulsions, and coma in humans (NCBI 2023r). Effects at 0.5 mg atropine were dry mouth and 

sweat inhibition (NCBI 2023r). Additional effects at 1 mg and 2 mg included increased heart rate 

and pupil dilation. At 5 mg, all the above symptoms were observed, with difficulty in speaking, 

swallowing, urinating, restlessness, headache, and fatigue. At 10 mg or greater doses, symptoms 

include blurred vision, flushed, hot, dry skin, hallucinations, delirium, and coma (NCBI 2023r). The 

eyes of treated animals may be sensitive to light from pupil dilation. 

Toxic effects in humans exposed to atropine and atropine sulfate have been seen following oral, 

intramuscular, intravenous, and ocular routes (Table 11). In humans, pupil dilation and 

hallucinations or distorted perception were observed at intramuscular doses of 0.001 mg/kg-bw

and 0.175 mg/kg-bw atropine, respectively (Table 11). 

An occupational exposure incident was illustrated by a 28-year-old respiratory therapist who 

administered atropine sulfate ten times over a 24-hour period (NCBI 2023r). She experienced 

anxiety, palpitations, dry mouth, dizziness, and blurred vision, and she was hot and flushed. She 

recovered in 48 hours. Of 240 clinical evaluations of 268 children exposed to doses up to 17-fold 

higher than standard doses of atropine for their age from accidental misuse of automatic atropine 

injectors, none experienced mortality or life-threatening complications (Amitai et al. 1992). Serum

atropine levels were 6.2 to 61 nanograms (ng)/mL, much higher than that observed after 

therapeutic doses (Amitai et al. 1992). Deaths followed ocular applications of 1.6 and 2 mg (Heath 

1950, Morton 1939) and oral doses of 100 mg (Legroux, 1962 (in French) (IPCS 2002)) in threeyear-old children. A 6-year-old boy ingested a 200 mg atropine sulfate solution and developed 

symptoms, including agitation, vomiting, and fever. The child received treatment and was 

released from the hospital after four days but continued to experience bilateral mydriasis for a 

week (Aliyev et al. 2015). Atropine sulfate levels in the blood 11 and 13 hours after admission 

were 1.93 μg/mL and below the limit of quantification, respectively. Tables 11a-b provide toxicity 

doses and effects of atropine and atropine sulfate in humans.

Table 11a. Toxicity doses and effects of atropine in humans: reported lowest dose causing a toxic 

effect (TDLo) and reported lowest dose causing lethality (LDLo).

Species Test type Dose Effect Reference

Human TDLo IM 0.001 mg/kg-bw Pupil dilation (NCBI 2023r)

Human TDLo Oral 0.033 mg/kg-bw Visual field changes, muscle weakness (NCBI 2023r)
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Man TDLo IM 0.175 mg/kg-bw Hallucinations, distorted perceptions (NCBI 2023r)

Man TDLo IV 0.014 mg/kg-bw Headache, blood pressure elevation (NCBI 2023r)

Man LDLo 

(unreported

)

0.143 mg/kg-bw (NCBI 2023r)

TDLo - Reported lowest dose causing toxic effect; LDLo - Reported lowest dose causing lethality; IM - Intramuscular; 

IV - Intravenous 

Table 11b. Toxicity doses and effects of atropine sulfate in humans: reported lowest dose causing 

a toxic effect (TDLo) and reported lowest dose causing lethality (LDLo).

Species Test type Dose Effect Reference

Child TDLo Oral 0.02 mg/kg-bw Decreased urine volume, 

behavioral excitement, change in 

heart rate

(NCBI 2023h)

Adolescent 

male

TDLo IV 0.028 mg/kg-bw Not provided (Lacouture et 

al. 1983)

Adult, male, 

and female

TDLo IM 0.028 mg/kg-bw Ataxia, increase in pulse rate (NCBI 2023h, 

White et al. 

1956)

Adult male TDLo 

(unreported)

0.014 mg/kg Behavioral effects (hallucination, 

distorted perceptions); headache

(Herschman et 

al. 1991, NCBI 

2023h)

Adult female TDLo 

(multiple)

0.044 mg/kg-bw Arrhythmia; behavioral effects 

(hallucinations, distorted 

perceptions)

(Elkins-Sinn 

1995)

Adult female TDLo Ocular 0.02 mg/kg-bw Arrhythmia (Elkins-Sinn 

1995)

Adult male LDLo Oral 357 mg/kg-bw Acute pulmonary edema (NCBI 2023h)

TDLo - Reported lowest dose causing toxic effect; LDLo - Reported lowest dose causing lethality; IM - Intramuscular; 

IV - Intravenous 

5.2.5.1 Acute Toxicity

Atropine and atropine sulfate can be toxic to mammals, depending on the dose and route of 

exposure. Atropine’s oral LD50 for rats, guinea pigs, and rabbits falls within USEPA’s acute toxicity 

category III, as does the intramuscular LD50 for rats (Table 12), indicating atropine is slightly toxic. 

Atropine’s oral LD50 for mice is in acute toxicity category II (Table 12), indicating atropine is 

moderately toxic. LD50 values for dermal and inhalation exposures and eye and skin irritation 

studies and skin sensitization studies are unavailable. 

Table 12. Mammalian toxicity of atropine and atropine sulfate.

Species Route Atropine LD50 Atropine 

Sulfate LD50

Reference

Brown Rat* Oral 500 mg/kg-bw 600 mg/kg-bw Atropine: (Lewis 1996)

atropine sulfate: (NCBI 

2023h)

Brown Rat* Subcutaneous 250 mg/kg-bw 540 mg/kg-bw (NCBI 2023h;r)

Brown Rat* Intramuscular 920 mg/kg-bw -- (Lewis 1996)
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Species Route Atropine LD50 Atropine 

Sulfate LD50

Reference

Brown Rat* Intravenous 73 mg/kg-bw 37 mg/kg-bw Atropine: (Lewis 1996)

atropine sulfate: (NCBI 

2023h)

Brown Rat* Intraperitoneal 280 mg/kg-bw 215 mg/kg-bw (Lewis 1996)

House Mouse* Oral 75 mg/kg-bw 468 mg/kg-bw (Lewis 1996)

House Mouse* Intradermal 550 mg/kg-bw -- (NCBI 2023r)

House Mouse* Subcutaneous -- 400 mg/kg-bw (NCBI 2023h)

House Mouse* Intravenous 30 mg/kg-bw 31 mg/kg-bw (Lewis 1996)

House Mouse* Intraperitoneal 30 mg/kg-bw 150 mg/kg-bw (NCBI 2023h;r)

Guinea pig Oral 1,100 mg/kg-bw -- (NCBI 2023r)

Guinea pig Subcutaneous -- 480 mg/kg-bw (NCBI 2023h)

Guinea pig Intraperitoneal 400 mg/kg-bw -- (NCBI 2023r)

Domestic Rabbit* Oral 600 mg/kg-bw -- (NCBI 2023r)

Domestic Rabbit* Intradermal 500 mg/kg-bw -- (NCBI 2023r)

Domestic Rabbit* Intramuscular -- 414 mg/kg-bw (NCBI 2023h)

Domestic Rabbit* Intravenous 50 mg/kg-bw 70 mg/kg-bw (NCBI 2023h;r)

Domestic Rabbit* Intraperitoneal -- 200 mg/kg-bw (NCBI 2023h)

Cat Intravenous -- 36 mg/kg-bw (NCBI 2023h)

Dog Intravenous -- 60 mg/kg-bw (NCBI 2023h)

* Domestic laboratory strains.

5.2.5.2 Sublethal and Chronic Toxicity

Standardized toxicity studies on the effects of subchronic and chronic exposure to atropine and 

atropine sulfate are unavailable. School children did not develop adverse effects on intraocular 

pressure or other injury effects after receiving atropine eyedrops daily for nearly five years (NCBI 

2023r). However, a chronic reference dose for atropine and atropine sulfate has not been

established.

In one study, male rats treated with 125 mg/kg-bw/day atropine for 10–17 days prior to mating 

with untreated females resulted in a lower pregnancy rate due to reduced male fertility (Sato et 

al. 2005). Female rats in gestation give atropine at days 7 to 19 led to adverse effects on the 

behavioral development of pups, namely deficiency in avoidance learning (Watanabe et al. 1985). 

Chick eggs injected with 0.6 to 1.5 mg atropine during the interval of 4 to 12 days incubation did 

not show signs of developmental effects (IPCS 2002). Atropine usage is short-term, and human 

fertility impairments have not been investigated. 

Atropine and atropine sulfate are not mutagenic (IPCS 2002), and atropine is not carcinogenic 

(Schmähl and M. Habs 1976). Atropine and atropine sulfate studies were negative in mutagenicity 

testing, and studies were summarized in IPCS (2002). In a long-term study on rats given 6 mg/kgbw/week atropine, atropine was not found to be carcinogenic (Schmähl and M. Habs 1976). 

Atropine is not listed as an endocrine disruptor (PAN 2018). In a laboratory study, atropine 
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treatment suppressed T-cell responses in spleen cells of rats exposed to approximately 2 mg/kgbw atropine/day subcutaneously for 3 weeks (Razani-Boroujerdi et al. 2008).

5.2.6 Dose-Response Assessment

5.2.6.1 Human Health Dose Response

The typical adult oral and parenteral (intramuscular, intravenous, or subcutaneous) dosage of 

atropine sulfate is 0.4–0.6 mg (range 0.1–1.2 mg) every 4–6 hours; for children, the oral and 

parenteral dose is 0.01 mg/kg-bw or 0.3 mg/m2 but not to exceed 0.4 mg every 4–6 hours (NCBI 

2023r). “The estimated lethal doses of atropine in adult humans are greater than or equal to 10 

mg” (as cited in (Jandrić et al. 2013)).

Intravenous doses of atropine sulfate at doses of 0.75 and 1.5 mg caused tachycardia in adult 

males and females ranging in age from 21 to 41 years, with a peak effect at 2 to 4 minutes followed 

by a slow decrease (Lönnerholm and Widerlöv 1975). Changes in blood pressure (increase in 

diastolic pressure) occurred at the highest dose (1.5 mg). At lower doses of 0.25 and 0.40 mg, 

subjects experienced bradycardia (slower than normal heart rate). At all doses, saliva secretion 

was inhibited with a clear dose-response relationship. In another study, seven adult males were 

given 0, 1.5, 3.0, and 6.0 mg/70 kg12 atropine sulfate dissolved in saline, and physiological and 

behavioral performance was measured over 24 hours (Higgins et al. 1989). Heart rate and pupil 

diameter increased as the atropine dose increased. Tests of behavioral performance (response 

rate and latency and correctly completing the task) showed a decrease as the atropine dose 

increased, with diminished performance across all behavioral tasks at the 6.0 mg dose and often 

at the 3.0 mg dose (Higgins et al. 1989). In general, at these two dose levels, the changes in 

behavioral performance peaked around 1.5 hours post-application and lasted for 7 to 9 hours,

with no effects observed at 24 hours (Higgins et al. 1989). Atropine’s percent bioavailability in the

body during use is 50 (Jjemba 2006), and the percentage of the parent compound excreted in 

clinical settings is 50, which is considered relatively high (Ali-Melkkilä et al. 1993).

5.2.6.2 Ecological Dose Response

Mammals

The acute toxicity of atropine and atropine sulfate to mammals is summarized in Section 5.2.4. In 

general, atropine and atropine sulfate have slight to moderate acute oral, inhalation, and dermal 

toxicity to mammals based on available data.

Intravenous infusion of 0.1 mg/kg atropine sulfate alone or five minutes prior to the intravenous 

infusion of 80 μg/kg-bw of xylazine in goats caused an increase in arterial blood pressure and 

heart rate (xylazine causes a decrease in blood pressure and heart rate) (Kokkonen and Eriksson 

1987). Atropine reduced salivation but did not inhibit saliva dripping (Kokkonen and Eriksson 

1987). Atropine did not suppress sedation in xylazine-treated goats, nor did it prevent respiratory 

12 The dose was normalized based on the mean body weight of the test subjects.
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suppression. Some goats became restless and shook their heads for two minutes after the 

injection of atropine (Kokkonen and Eriksson 1987).

Intravenous injection of 0.2 mg/kg-bw atropine in twelve male and female dogs (mean weight of 

12.5 +/- 0.5 kg) caused an increase in heart rate from around 87 beats/minute to around 244 

beats/minute within two minutes and remained at this rate for six minutes before decreasing 

(Chassaing et al. 1979). Atropine disappearance in the blood was rapid within the first 20 minutes,

and the heart rate decreased during this time (Chassaing et al. 1979). In another study, dogs (10 

to 20 kg in weight) given 0.5 mg/kg-bw atropine sulfate intravenously experienced salivation 

inhibition, decreased gastric secretion, and tachycardia around 160 beats/min greater than normal 

within 15 seconds of administration (Rush et al. 1970). There were no other observed changes in 

behavior other than restlessness (Rush et al. 1970).

Atropine had different behavioral disturbances in dogs at five different ages (newborn, 3 weeks, 

6 weeks, 3 months, and adult) due to the development of two enzymes (choline acetyltransferase 

and cholinesterase) as the animal matures (Winbladh 1973). Behavioral disturbances in 6-week 

old, 3-month old, and adult dogs given 0.5 mg/kg-bw atropine included ataxia, nonresponsiveness, non-retreating behavior, and increased motor activity (Winbladh 1973). In 

newborn dogs, atropine had no effect at doses from 0.5 to 5 mg/kg-bw (Winbladh 1973). In 3-

week old dogs, those that were more mature had symptoms similar to adult dogs, while less 

mature dogs did not display symptoms even at the 5 mg/kg-bw dose (Winbladh 1973). Table 10

summarizes recommended atropine sulfate dosages in several animals.

Birds

Information on the acute toxicity of atropine and atropine sulfate in wild birds is limited. Atropine 

sulfate was mildly toxic to 14–20 day old chickens dosed intramuscularly into pectoral muscles 

with 100 mg/kg-bw atropine sulfate (Shlosberg et al. 1997). The researchers did not see adverse 

short-term or long-term effects at doses below 100 mg/kg-bw (0.5, 25, 50 mg/kg-bw). Atropine 

treatment in ratites (large flightless birds such as ostrich) to manage bradycardia is variably 

effective (West et al. 2007); xylazine may cause bradycardia in ratites. In a study evaluating drugs 

that dilate pupils in wild birds, double-crested cormorants around two to three months old were 

given 1% (4 drops) of atropine in the eye at four 15-minute intervals (Loerzel et al. 2002). No 

effect on pupil diameter or other side effects was observed.

Reptiles and Terrestrial Phase Amphibians 

Information on the acute and subchronic toxicity of atropine and atropine sulfate in reptiles and 

terrestrial-phase amphibians is lacking.

Invertebrates

Atropine sulfate fed (3mg/1 g diet) or applied daily for 2–5 days to the mesothorax in 1 μl (1x10-2

M aqueous acetone solution) doses to sixth-instar western spruce budworms (Choristoneura 

occidentalis) did not cause delays in maturity, developmental abnormality, or mortality (Smith 

1971).
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Aquatic Vertebrates and Invertebrates

Available data suggest that atropine and atropine sulfate are practically non-toxic to fish and 

aquatic invertebrates. Based on the effects on heart rate during a 30-minute exposure, rainbow 

trout at embryonic stages 22 and 29 and larval stage 30 have a NOEC of 28.94 mg/L atropine 

sulfate (USEPA 2019a). In the same study, a LOEC of 28.94 mg/L atropine sulfate was based on 

increased heart rate at embryonic stage 26 and larval stage 32. Atropine is practically non-toxic 

to zebrafish with an EC50 value of 559.1 mg/L and a no observable adverse effect concentration 

(NOAEC) of 400 mg/L atropine (Ali et al. 2014). USEPA classifies atropine as teratogenic based 

on the zebrafish assay. 

An LC50 was not calculated for brine shrimp (Artemia salina) because toxicity was not observed 

at the highest dose of atropine sulfate tested (>1,000 mmol/L) (Barahona and Sánchez-Fortún 

1999). In another study, the LC50 for A. salina was 22,700 μmol/L atropine sulfate (Calleja et al. 

1994). Atropine sulfate is practically non-toxic to the freshwater cladoceran, D. magna, with

reported LC50 values of 354 mg/L and 104 mg/L at 24 and 48 hours, respectively (Carvalho et al. 

2003). In another study using D. magna, the 24-hour EC50 value was 0.372 +/-0.038 mM atropine 

sulfate with recovery (i.e., mobility) observed 3 hours after exposure (Lilius 1994). In another 

study, the EC50 for D. magna was 513 μmol/L (Calleja et al. 1994). In laboratory studies, the

marine bacterium Photobacterium phosphoreum had LC50 values of 8,010 μmol/L atropine sulfate 

(Calleja et al. 1994). For freshwater species, the LC50 for freshwater rotifers (Brachionus 

calyciflorus) was 481 μmol/L and for fairy shrimp (Streptocephalus proboscideus), 951 μmol/L 

atropine sulfate (Calleja et al. 1994).

5.3 Doxapram

5.3.1 Chemical Description and Product Use

Doxapram (CAS No. 309-29-5; C24H30N2O2; chemical structure in Appendix 3) is a central 

respiratory stimulant that affects the carotid and aortic chemoreceptors and the medullary 

respiratory centers (Kreeger and Arnemo 2012). WS uses doxapram to stimulate breathing to 

speed the recovery of the animal after xylazine sedation and Telazol® (tiletamine + zolazepam) 

anesthesia. However, it is not a pure antagonist because it does not operate on the same 

receptors as the agonists. Doxapram is also used to reverse hypoventilation or apnea caused by 

barbiturate anesthesia in dogs and anesthesia from ketamine, ketamine-xylazine, ketaminepromazine, and opioids such as carfentanil (Kreeger and Arnemo 2012). The duration of 

respiratory stimulation is brief (5-10 minutes); doses may be repeated every 15 minutes (Kreeger 

and Arnemo 2012). Doxapram is sold as Dopram-V® (veterinary formulation) and Dopram® 

(human formulation). Each 1 mL of doxapram injection contains 20 mg doxapram HCl, 0.9% 

benzyl alcohol (preservative), and water for injection (Drugs.com 2023a, FDA 2005). WS

administers doxapram intramuscularly by hand using a syringe to already immobilized animals. 

5.3.2 Physical and Chemical Properties
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Doxapram is an oral or injectable colorless liquid (APHA 2015). It has a pH between 3.5 and 5 

(Drugs.com 2023a) and a melting point of 217–219oC (NCBI 2023o). Its molecular weight is 378.5 

g/mol (NCBI 2023o). Doxapram is sparingly soluble13 (NCBI 2023o) and stable and non-reactive 

under normal use, storage, and transport (Boehringer Ingelheim 2018). It is incompatible with 

strong oxidizing agents (Boehringer Ingelheim 2018). Doxapram (e.g., Dopram-V®, Dopram®) is 

sold in 20 mg/mL concentrations (APHA 2015, USDA APHIS 2019b), and its preservative is 

benzyl alcohol (DOPRAM-V 2013). The solution contains doxapram HCl (CAS No. 7081-53-0; 

(APHA 2015). 

5.3.3 Environmental Fate

We were unable to find information in the scientific literature on the environmental fate of 

doxapram in soil, water, and air. A literature search revealed that doxapram is not readily 

biodegradable (DrugBank 2023b).

5.3.4 Metabolism

Doxapram stimulates breathing but can also be used to speed up the recovery of an animal by 

increasing the metabolism of the immobilizing drug. While Telazol has no antagonist, doxapram 

(not a true antagonist) can be used for this purpose (USDA APHIS 2019b). In dogs given 10 

mg/kg and 20 mg/kg doxapram intravenously, blood concentrations of doxapram and its 

metabolites were at peak levels immediately after injection and declined rapidly in the first hour. 

The metabolism of doxapram decreased after the first hour allowing for the presence of doxapram 

after 24 hours. A dog given doxapram with radioactive carbon had feces with 29% of the 

administered radioactivity after 48 hours and an additional 9% the following 24 hours (DOPRAMV 2013).

5.3.5 Hazard Identification

Doxapram is FDA approved for humans. Doxapram stimulates respiration by primarily affecting 

the brain stem and is used to speed awakening and return reflexes after anesthesia or to stimulate 

respiration during and after general anesthesia (DOPRAM-V 2013). Dogs and horses have 

dramatic responses to doxapram, while respiratory stimulation is moderate in cats and slight in 

rats (DOPRAM-V 2013). Respiratory stimulation was observed in anesthetized dogs after 

intravenous, intramuscular, intraperitoneal, oral, sublingual, and subcutaneous administration 

(DOPRAM-V 2013). Adverse effects include seizures, hypertension, tachycardia, and arrhythmia.

5.3.5.1 Acute Toxicity

Doxapram is in category III for acute oral toxicity (Boehringer Ingelheim 2018). The acute oral 

LD50 is 261 mg/kg-bw in rats, 270 mg/kg-bw in house mice, and 150 mg/kg-bw in dogs (Table 9). 

13 Sparingly soluble materials are those that require 30 to 100 ml solution to dissolve 1 g of material.
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5.3.5.2 Sublethal and Chronic Toxicity

Reproduction studies in rats receiving oral or intramuscular doses of doxapram up to 1.6 times 

the human dose have revealed no evidence of impaired fertility or harm to the fetus (FDA 2005).

5.3.6 Dose-Response Assessment

5.3.6.1 Human Health Dose Response

Following a single intravenous injection of doxapram HCl at 0.5–1.0 mg/kg, respiratory stimulation 

generally occurs within 20–40 seconds with peak effect at 1–2 minutes. The duration of the effect 

varies from 5–12 minutes (FDA 2005). Side effects from the use of doxapram that are indicative 

of subconvulsive central nervous system stimulation include hypertension, tachycardia, 

arrhythmias, coughing, sneezing, vomiting, itching, tremors, muscle rigidity, sweating, flushing, 

and hyperpyrexia (NCBI 2023o). Doxapram overdose symptoms include tachycardia, skeletal 

muscle hyperactivity, and enhanced deep tendon reflexes (NCBI 2023o).

5.3.6.2 Ecological Dose Response

Information is lacking on the effects of doxapram on aquatic species and wildlife. 

5.4 Naltrexone

5.4.1 Chemical Description and Product Use

Naltrexone (CAS No. 16590-41-3; C20H23NO4; chemical structure in Appendix 3) is designated an 

orphan drug by the US Food and Drug Administration (FDA) in the maintenance of alcohol and 

opiate cessation (NCBI 2023y). Naltrexone is a competitive inhibitor of the opioid receptors and 

displaces opioid drugs from these receptors, thus reversing their effects (NCBI 2023y). 

Naltrexone can antagonize all opiate receptors. There are FDA-approved products for oral and 

intramuscular administration that contain naltrexone, but the only approved veterinary drug that 

contains naltrexone is Trexonil® (intramuscular). The human drug oral dosage forms (tablets)

could be prescribed for extra-label use in animals by a veterinarian under certain circumstances.

Subcutaneous treatments are not approved by the FDA and can result in serious side effects 

(Alkermes Inc. 2016). WS uses naltrexone to reverse the effects of sedative immobilization drugs 

such as butorphanol tartrate and nalbuphine and those drugs in the combinations BAM and NAM. 

Naltrexone is long-lasting compared to other opioid antagonists. It is preferred in wildlife when 

potent opioids are used because it minimizes the potential re-narcotization from long-lasting 

opioids and minimizes the need to re-dose animals, particularly when personnel safety concerns 

exist (Plumb 2018). Naltrexone is also used to antagonize butorphanol in swine (West et al. 2007).
ACCESSORY DRUGS 72

5.4.2 Physical and Chemical Properties

Naltrexone is an insoluble solid at room temperature, with a melting point of 168–170°C (O'Neil 

2013). As hydrochloride salt, the solubility of naltrexone is 100 mg/mL (McEvoy 1990). The 

molecular weight of naltrexone a.i. is 341.4 g/mol, with a vapor pressure of 3.11x10-11 and a 

Henry's Law constant of 4.22x10-19 atm-m3

/mol at 25°C (NCBI 2023v;y).

5.4.3 Environmental Fate

Naltrexone's use in the maintenance of animal populations may result in its release to the 

environment through various waste streams (NCBI 2023y). If released into water, naltrexone is 

expected to adsorb to suspended solids and sediment based on the estimated organic carbon 

octanol-water partition coefficient (Koc) (NCBI 2023v). Hydrolysis is not expected to be a 

significant environmental fate process since this compound lacks functional groups that hydrolyze 

under environmental conditions (pH 5 to 9) (NCBI 2023v). Volatilization from water surfaces is 

also not expected based upon this compound's acid dissociation constant value, and if released 

to air, an estimated vapor pressure of 3.1x10-11 mm Hg at 25°C indicates naltrexone will exist 

primarily in the particulate phase (NCBI 2023v). Particulate-phase naltrexone will be removed 

from the atmosphere by wet or dry deposition. Naltrexone is not expected to be susceptible to 

direct photolysis by sunlight or undergo hydrolysis in the environment (NCBI 2023v), and if 

released to soil, naltrexone is expected to have low mobility based upon an estimated (Koc) of 

1,040 (USEPA 2012). The acid disassociation constant (pKa) values of naltrexone are 8.38 and 

9.93 (Kaufman et al. 1975), indicating that this compound will exist almost entirely in the cation 

form in the environment and cations generally adsorb more strongly to soils containing organic 

carbon and clay than their neutral counterparts (NCBI 2023v). Volatilization from moist soil is not 

expected because the compound exists as a cation, and cations have a propensity not to volatilize 

(NCBI 2023v). An estimated bioconcentration factor (BCF) of 9 suggests a low potential for 

bioconcentration in aquatic organisms (NCBI 2023v). Occupational exposure to naltrexone may 

occur through inhalation of dust during production, storage, and transport. Risks of accidental 

exposure to naltrexone primarily involve those who prescribe, prepare or administer the drug 

(NCBI 2023v). Biodegradation data in soil or water are not available.

5.4.4 Metabolism

In humans, naltrexone is metabolized in the liver principally by reduction of the 6-keto group 

of naltrexone to 6-beta-naltrexol (6-beta-hydroxynaltrexone) (American Society of Health-System 

Pharmacists 2017). Naltrexone metabolites undergo conjugation with glucuronic acid. The major 

fraction of total drug and metabolites in both plasma and urine consists of conjugated metabolites 

(American Society of Health-System Pharmacists 2017, NCBI 2023y). The primary route of 

elimination of the parent drug and its metabolites is the kidney (53% to 79% of the dose) (T3DB 

2023). However, urinary excretion of unchanged naltrexone accounts for less than 2% of an oral 

dose, and fecal excretion is a minor elimination pathway (T3DB 2023). The renal clearance for 

naltrexone ranges from 30 to 127 mL/min. It suggests that renal elimination is primarily by 

glomerular filtration with a half-life of 4 hours for naltrexone and 13 hours for the active metabolite 

6 beta-naltrexol (T3DB 2023).
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Naltrexone may also undergo partial reabsorption by the renal tubules. Most urinary excretion 

of naltrexone occurs within the first 4 hours after oral administration. Following the oral 

administration of 50 mg of radiolabeled naltrexone in one patient, approximately 93% of the 

radiolabeled dose was excreted within 133 hours; about 79 and 14% were excreted in urine and 

feces, respectively (NCBI 2023v). In raccoons, residues of naltrexone were detected in 

homogenized muscle, fat, liver, and kidney tissue 2, 4, and 6 days post-administration of 0.233 

mg/kg naltrexone to reverse butorphanol or nalbuphine (Johnson et al. 2023b). 

Cases of hepatitis and clinically significant liver dysfunction have been observed in association 

with naltrexone hydrochloride exposure. When patients exposed to naltrexone presented with 

elevated transaminases, other potential coexisting causative or contributory conditions were often

present, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, or 

concomitant usage of other potentially hepatotoxic drugs (NLM 2017a). 

Symptoms of opioid withdrawal appear within five minutes of naltrexone hydrochloride exposure 

and last up to 48 hours. Confusion, somnolence, and visual hallucinations have occurred. 

Significant fluid losses from vomiting and diarrhea have required intravenous fluid administration.

(NLM 2017a). Other adverse effects of naltrexone potentially include abdominal cramping, 

nausea, vomiting, nervousness, insomnia, joint or muscle pain, skin rashes, and itchy skin (Plumb 

2018). 

5.4.5 Hazard Identification

5.4.5.1 Acute Toxicity

Acute naltrexone toxicity in mice, rats, and dogs resulted in death secondary to tonic-clonic 

seizures and/or respiratory failure (NCBI 2023v). The oral LD50 in mice is 1.1 g/kg-bw, with death 

occurring from respiratory depression or tonic-clonic seizure (Plumb 2018). The subcutaneous 

injection LD50 in dogs is 200 mg/kg-bw (Plumb 2018). Weight loss was observed in monkeys 

following the subcutaneous administration of 100 mg/kg-bw of naltrexone. Prostration, seizures, 

and death were observed in monkeys after 300 mg/kg-bw subcutaneous doses of naltrexone 

(NCBI 2023y). Hypoactivity, salivation, and emesis occurred in monkeys following oral 

administration of 1 g/kg-bw doses. Seizures and death occurred following oral administration of 3

g/kg-bw (American Society of Health-System Pharmacists 2017). 

Bradycardia has been observed following intravenous (iv) naltrexone hydrochloride doses of 5-

80 μg/kg-bw in unanesthetized dogs. In naltrexone hydrochloride-treated cats (1 mg/kg-bw), total 

brain oxygen consumption was reduced by approximately 48%, and blood flow to the entire brain 

region decreased by about 40% (American Society of Health-System Pharmacists 2017). 

Increases in mean arterial pressure, cardiac output, stroke volume, and left ventricular contractility 

were observed in dogs with hypovolemic shock following administration of naltrexone 

hydrochloride doses ranging from 2.5–10 mg/kg-bw as a rapid intravenous injection or 2 mg/kg-
ACCESSORY DRUGS 74

bw rapid intravenous injection followed by an intravenous infusion of 2 mg/kg-bw per hour for 4 

hours (American Society of Health-System Pharmacists 2017, NCBI 2023v). 

5.4.5.2 Subacute and Chronic Toxicity

In a 2-year study of the carcinogenic potential of naltrexone, increases in the frequency of 

mesotheliomas in male rats and tumors of vascular origin in both male and female rats were 

observed. No evidence of carcinogenicity was observed in several other 2-year studies in mice 

or rats receiving naltrexone dosages of 30 or 100 mg/kg-bw daily (47 or 150 times greater than 

the usual dosage in humans), respectively (NCBI 2023v). 

5.4.6 Dose-Response Assessment

5.4.6.1 Human Health Dose Response

Oral naltrexone treatment has been observed to result in hormonal changes in women (50 mg), 

and intramuscular naltrexone (intramuscular) has also been observed to potentially be 

hepatotoxic, resulting in a hepatotoxicity severity grade of 3 (NCBI 2023v). Patients receiving 800 

mg of naltrexone hydrochloride daily for up to 1 week in one study showed no evidence of toxicity. 

However, lower dosages reportedly have been hepatotoxic in some patients. No serious adverse 

effects were observed following the administration of single naltrexone doses of up to 784 mg (as 

the extended-release intramuscular injection) in several healthy individuals (American Society of 

Health-System Pharmacists 2017). 

High doses of naltrexone greater than 100 mg/kg-bw have been observed to cause excess 

salivation, depression/reduced activity, tremors, and convulsions (T3DB 2023). 

In a study of 250 male opioid-dependent patients, non-statistically significant changes in liver 

enzyme levels were most often observed in hepatitis-C-positive patients. The majority of the 

elevations greater than three times the upper limit of normal occurred in patients with chronic HCV 

infection (Mitchell Jr et al. 2012). 

Abrupt opioid withdrawal may lead to systemic sequelae, including acute liver injury. It is advised 

to seek medical attention if people exposed to naltrexone experience symptoms of acute hepatitis 

(NCBI 2023v). Additionally, subcutaneous injection of naltrexone can cause severe site-related 

reactions. Only oral and intramuscular treatments are approved by the FDA (Prescriber's Desk 

Reference 2023). 

Tolerance to naltrexone can lead to possible accidents or injury due to side effects such as loss 

of coordination, slowed reaction time, sleepiness, impaired judgment, overdose, and death (T3DB 

2023).

5.4.6.2 Ecological Dose Response
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In veterinary medicine, naltrexone (2–5 mg/kg-bw oral) has been used to treat behavioral 

disorders (Plumb 2018). 

Anesthesia of wild ass with a single 3-mL dart containing 4.4 mg etorphine, 10 mg detomidine, 

and 10 mg butorphanol was reversed with an i.v. combination of 200 mg naltrexone and 20 mg 

atipamezole. The reversal was rapid and smooth, with animals standing and alert in approximately

2 minutes following the administration of the antagonists (West et al. 2007). 

Naltrexone has been observed to increase the CNS effects of yohimbine, e.g., anxiety, tremors, 

nausea, palpitations, and cortisol levels (NCBI 2023v). In a Sokolowska-Mikolajczyk 2002 study 

to determine the role naltrexone has on endogenous opioid peptides in luteinizing hormone (LH) 

secretion in fish, sexually mature male Eurasian (common) carp were intravenously injected with 

naltrexone-opioid receptor antagonist (5 or 50 μg/kg-bw) in the period of natural spawning (June) 

or gonad recrudescence (December). Blood samples were taken every minute, up to 10 min after 

the naltrexone injection. It was observed that in June, naltrexone significantly lowered LH levels 

in comparison to saline-injected males. In December, there were no differences between saline 

and naltrexone-injected carps. These results detailed that, in male carp, LH secretion under the 

influence of naltrexone depends on the stage of gonad maturity and also suggests that the 

feedback of gonadal steroids on LH release could be mediated by the endogenous opioids 

(Sokolowska-Mikolajczyk et al. 2002). 

5.5 Tolazoline

5.5.1 Chemical Description and Product Use

Tolazoline HCl (CAS 59-97-2; C10H13CIN2; chemical structure in Appendix 3) is a combination 

alpha-1 and alpha-2 antagonists that reverse the sedative effects of xylazine HCl. It belongs to 

the imidazole derivative group and competitively inhibits alpha-adrenoreceptors. Tolazoline HCl 

is used in human medicine (PrisolineTM, 25 mg/mL and for domestic animals such as horses and 

cattle (TolazineTM). Tolazoline was approved by the FDA in 1996 in a 100 mg/mL concentration, 

but it is routinely compounded and available in a 200 mg/mL concentration in 30 mL multiple-use 

vials. In wildlife applications, tolazoline has been shown to be effective for use in equids and 

cervids (Monteith et al. 2012, Plumb 2018). To reverse the sedative effects of xylazine HCl in 

horses, 4.0 mg/kg-bw of tolazoline HCl is used (Plumb 2018). In cervids, 4 mg/kg-bw of tolazoline 

reversed xylazine in deer, reducing time to standing (Monteith et al. 2012). WS would administer

tolazoline through intramuscular or intravenous hand injection with a syringe and needle to 

reverse the sedative effects of xylazine in wildlife, including ungulates and carnivores, when 

needed and for the appropriate species (USDA APHIS 2019b). 

5.5.2 Physical and Chemical Properties

Tolazoline is a crystalline solid. A stock solution may be made by using an organic solvent such 

as ethanol (Cayman Chemical 2022c). WS uses tolazoline as an injectable solution. It has a 

molecular weight of 196.7 g/mol (Cayman Chemical 2022c). The commercially available human 

injection has a pH between 3 and 4 (Mikota and Plumb 2017). Tolazoline HCl has a melting point 
ACCESSORY DRUGS 76

of 174°C. Its experimental log Kow is 2.65, indicating that the drug is more lipophilic than 

hydrophilic (DrugBank 2021a). Tolazoline is soluble in water, with solubility ranging from 0.373–

1.36 g/L, and the pKa is 10.3 (NCBI 2023e). The estimated vapor pressure is 2.4x10-6 mmHg, 

and the estimated Henry’s Law constant is 5.18x10-8 atm-m3

/mol, both at 25°C (USEPA 2023d). 

The drug should be stored at a controlled room temperature of -20°C for long-term storage 

(Cayman Chemical 2022c). 

5.5.3 Environmental Fate

Information is lacking in the scientific literature on the fate and persistence in soil, water, and air 

of tolazoline. Tolazoline is not volatile based on its vapor pressure. The estimated biodegradation 

half-life for tolazoline is 3.36 days (USEPA 2023d). The estimated soil adsorption coefficient (Koc) 

is 141 L/kg, indicating it is moderately mobile in soil, and the estimated bioconcentration factor is 

5.07 (ComTox), indicating tolazoline has a low risk of bioaccumulation.

5.5.4 Metabolism

The biological half-life for tolazoline is 313 hours and is mostly excreted in urine within 2–4 weeks 

following administration (as cited in (USDA AMS 2019)). In horses given a 4 mg/kg-bw dose of 

tolazoline intravenously, the elimination half-life was 2.08 hours (Plumb 2018). 

5.5.5 Hazard Identification

Information on the acute toxicity and sublethal and chronic toxicity of tolazoline in the scientific 

literature was limited. The biological half-life for tolazoline is 313 hours and is mostly excreted in 

urine within 2–4 weeks following administration (as cited in (USDA AMS 2019)). Tolazoline is in 

toxicity category II for acute oral toxicity study (Cayman Chemical 2022c). The oral LD50 in rats is 

1,200 mg/kg-bw, and in house mice, 400 mg/kg-bw (Table 9) (Cayman Chemical 2022c). It is 

listed as category II for skin corrosion and irritation (Cayman Chemical 2022c). We did not find 

published information on the carcinogenicity of tolazoline. 

5.5.6 Dose-Response Assessment

5.5.6.1 Human Health Dose Response

In humans, tolazoline causes vasodilation and is used to treat hypo- and hypertension, respiratory 

distress in newborns, and congenital heart disease (as cited in (USDA AMS 2019)). Studies on 

the toxicity, lethal dosages, and carcinogenicity of tolazoline in humans are unavailable in the 

scientific literature. 

5.5.6.2 Ecological Dose Response

In veterinary medicine, tolazoline is used to reverse the effects of xylazine. Tolazoline can result 

in tachycardia, defecation, vomiting, salivation, and edema (Kreeger and Arnemo 2012). Studies 

on the toxicity and lethal dosages in animals are limited (Table 9). Tolazoline is practically nontoxic 

to fish, with a 96-h LC50 of 354 mg/L in fathead minnows (Pimephales promelas) (Sigma-Aldrich 
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Corporation 2019). Side effects of tolazoline include increases in blood pressure, peripheral 

vasodilation, and tachycardia. 

Horses given 1, 3, and 5 times the recommended dose of 4 mg/kg-bw tolazoline (without prior 

xylazine dosing) every 6 hours for 3 doses had gastrointestinal disturbances (Akorn Animal 

Health). No hematologic, serum, or urinalysis measurements were affected by tolazoline at doses 

equal to or less than the 5 times dose or 20 mg/kg-bw (Akorn Animal Health). Overdoses at 5 

times the recommended rate for tolazoline have been linked to death in horses (Akorn Animal 

Health). After an intravenous tolazoline dose of 4 mg/kg-bw in horses, heart rate decreased 

beginning 2 minutes post-injection, reaching its lowest point 45 minutes post-injection (Plumb 

2018). Serum glucose concentrations increased through 1.5 hours post-injection (Plumb 2018). 

The withdrawal period is 8 days after administering to livestock intended for slaughter, and a milk 

discard period of four days in dairy animals (Plumb 2018, USDA AMS 2019). 

5.6 Yohimbine Hydrochloride

5.6.1 Chemical Description and Product Use

Yohimbine HCl (CAS No. 65-19-0; C21H26N2O3·HCl; chemical structure in Appendix 3), a plant 

alkaloid (NCBI 2023a), easily penetrates the blood-brain barrier and causes reversal of the 

sedative effects of xylazine usually within 2–10 minutes (IPCS 1992). Yohimbine also reverses 

cardiac side effects, such as arrhythmia and bradycardia, which can occur as a result of xylazine 

(Akorn Animal Health 2018a). Yohimbine is not a specific alpha-adrenergic antagonist; therefore, 

it can cause cholinergic, serotonergic, and dopaminergic receptor activity. Because yohimbine 

and other adrenergic antagonists do not fully antagonize ketamine, they should not be 

administered to animals until ketamine has had adequate time to metabolize in the animal 

(Kreeger and Arnemo 2012). Yohimbine HCl was approved by the FDA in 2 mg/mL and 5 mg/mL 

strengths and is compounded in 30 mL multiple-use vials. In cervids, yohimbine HCl is 

administered intravenously at a dose of 0.2–0.3 mg/kg-bw (FDA 2024). Veterinary formulations 

of yohimbine include Yobine® (Akorn Animal Health 2018b) and Antagonil® (NCBI 2023a). The

recommended dosage for dogs to reverse xylazine is 0.11 mg/kg (NADA 140-866 Yobine

Injectable Solution) (Akorn Animal Health 2018b). 

Yohimbine was first used successfully to reverse the sedative effects of xylazine in cervids. The 

drug produces consistent results in non-domestic members of the dog and cat families (Canidae 

and Felidae), but it produces inconsistent results in bovids (Bovidae). WS administers yohimbine 

HCl intravenously to immobilized animals to reverse the sedative effects of xylazine in wolves and 

other predators and other appropriate wildlife species, but not necessarily ungulates or hoofed 

mammals. Yohimbine can be injected intramuscularly, if necessary, but it will be slower to act 

(USDA APHIS 2019b). 

5.6.2 Physical and Chemical Properties

Yohimbine HCl is a white to off-white, water-soluble powder with a molecular weight of 390.90 

g/mol. Its melting point is 288–290°C. Aqueous solutions have a neutral pH (Sigma-Aldrich 
ACCESSORY DRUGS 78

Corporation 2002a). Its predicted solubility in water is 0.35 g/L (HMDB 2019c). The experimental 

log Kow for yohimbine is 2.73 indicating the drug is more lipophilic than hydrophilic (HMDB 2019c). 

Yohimbine HCl solutions are light-sensitive (Sigma-Aldrich Corporation 2002a).

5.6.3 Environmental Fate

We were unable to find information in the scientific literature on the degradability, bioaccumulative 

potential, or mobility in air and soil for yohimbine HCl. Yohimbine is slightly soluble in water (IPCS 

1992). The predicted median biodegradation half-life is 144 days, the estimated soil adsorption 

coefficient (Koc) 1.37x104 L/kg, indicating it is hardly mobile in soil, and the estimated 

bioconcentration factor 14.2 (USEPA 2023c).

5.6.4 Metabolism

Owen et al. (1987) researched the impact that oral administration of a single dose of yohimbine 

HCl had on eight young males, and results showed the drug was rapidly absorbed (absorption 

half-life 11 min) into systemic circulation and rapidly eliminated from plasma (elimination half-life 

36 min). Less than 1% of the parent compound in the dose was recovered in the urine in a 24-

hour period, suggesting that yohimbine is primarily eliminated through hepatic metabolism 

(Hedner et al. 1992, Owen et al. 1987). Yohimbine is metabolized into 11-hydroxy-yohimbine and 

10-hydroxy-yohimbine. The 11-hydroxy-yohimbine metabolite is the only one detected in plasma 

and has alpha-2 adrenergic antagonist properties (Berlan et al. 1993, Federal Institute for Risk 

Assessment 2016, Le Corre et al. 1999). 

The pharmacokinetics of yohimbine HCl varies between individuals. Routine administration of 

yohimbine HCl three times daily for 6 days had no effect on pharmacokinetics (Sturgill et al., 1997 

in (Federal Institute for Risk Assessment 2016)). Oral bioavailability data show significant 

variation, ranging from 7% to 87% (EFSA 2013). The consumption of fat-rich food has the 

potential to reduce the absorption of yohimbine HCl (Grasing et al. 1996).

The mean half-life of yohimbine HCl injection is 46.7 ± 24.4 min in steers, 76.1 ± 23.1 min for a 

small dose, and 52.8 ± 27.8 min for a large dose in horses, and 104.1 ± 32.1 min for dogs 

(Jernigan et al. 1988). Yohimbine HCl produced no behavioral changes in steers and horses. 

However, 1 to 2 minutes after dogs were injected, numerous dogs had increased respiratory rates, 

muscle tremors, hyperemic mucous membranes, salivation, emesis, and mildly agitated behavior. 

These symptoms lessened after 15 to 20 minutes, and normal behavior returned after 90 to 150 

minutes (Jernigan et al. 1988). 

5.6.5 Hazard Identification

Yohimbine has been used medicinally by people for centuries at low doses, but side effects could 

be seen at higher doses. Yohimbine readily stimulates the central nervous system (EFSA 2013), 

but can cause side effects such as muscle tremors, increased blood pressure, dizziness, vomiting, 

anxiety, and nausea (Federal Institute for Risk Assessment 2016). Other adverse effects include 

excitation, insomnia, hypertension, and tachycardia. FDA, though, approved the use of yohimbine 

HCl for humans. Doctors may prescribe yohimbine to humans for the treatment of sexual 
ACCESSORY DRUGS 79

dysfunction, as an aphrodisiac, or for fatigue and exhaustion (Kommission, 1987, 1990 in (Federal 

Institute for Risk Assessment 2016)). In humans, yohimbine is not recommended for use with 

antidepressants and other mood-altering drugs. 

Yohimbine is effective for reversing xylazine in horses, cats, and dogs but is less effective in 

ruminants. Yohimbine is not as effective at reversing newer drugs such as medetomidine (West 

et al. 2007). Research indicates that dogs receiving five times the recommended dose of 

yohimbine (0.55 mg/kg) experienced transient seizures and muscle tremors. 

5.6.5.1 Acute Toxicity

Yohimbine’s oral LD50 value (43 mg/kg-bw) and subcutaneous LD50 value (20 mg/kg-bw) in house 

mice indicate it is highly toxic (Table 9). The reported lowest dose causing lethality (LDLo) of 

yohimbine given to mice and rabbits intravenously was reported to be 16 mg/kg-bw and 11 mg/kgbw, respectively (Table 9). The LDLo for subcutaneous administration of yohimbine in rabbits was 

50 mg/kg-bw (IPCS 1992). 

5.6.5.2 Sublethal and Chronic Toxicity

Dogs tolerated yohimbine at 3 and 5 times the intended dose, but at the 5x dose, dogs displayed 

brief seizures and muscle tremors, though no lasting effect (Akorn Animal Health 2018b). Data is 

unavailable for yohimbine’s carcinogenicity, teratogenicity, and mutagenicity (IPCS 1992).

5.6.6 Dose-Response Assessment

5.6.6.1 Human Health Dose Response

A study evaluating the effectiveness and safety of a high dose of yohimbine HCl (36 mg/day for 

25 days) in 29 men resulted in drug-related adverse effects in 2 patients (7%). One man 

experienced a hypertensive crisis, while the other experienced severe palpitation (Kunelius et al. 

1997). Another study of healthy volunteers receiving oral yohimbine of 20 or 40 mg caused dosedependent increases in blood pressure, heart rate, and plasma noradrenaline (Murburg et al., 

1991 in (EFSA 2013)). In another situation, a 37-year-old bodybuilder was admitted to the hospital 

with acute neurotoxicity after ingesting 5 g of yohimbine. The patient experienced malaise, 

vomiting, loss of consciousness, and repeated seizures but recovered (Giampreti et al., 2009 in

(EFSA 2013)).

5.6.6.2 Ecological Dose Response

In zebrafish larvae, yohimbine HCl had an EC50 value of 14.5 mg/L and a NOAEC of 10 mg/L (Ali 

et al. 2014). Phenotypic abnormalities included pericardial edema (fluid retention), yolk sac 

edema, dispersed pigment cells, and an uninflated swim bladder, and in this zebrafish assay, 

yohimbine HCl was teratogenic (Ali et al. 2014).
EUTHANASIA AGENTS 80

6 EUTHANASIA AGENTS

WS uses chemical agents to euthanize animals for postmortem disease diagnosis or 

investigations or when an animal is injured. WS personnel refer to WS Directive 2.505 Lethal 

Control of Animals for the current policy on euthanasia. WS follows the AVMA Guidelines on 

Euthanasia as required by WS policy.

Table 13. Acute toxicity values for euthanasia drugs.

Chemical Test Species Test Type LD50 (LC50) Reference

Potassium 

Chloride

Brown Rat* Acute oral 3,020 mg/kg-bw OECD, 2001

Brown Rat* Intravenous 142 mg/kg-bw OECD, 2001

House Mouse* Intravenous 117 mg/kg-bw OECD, 2001

Brown Rat* Intraperitoneal 660 mg/kg-bw OECD, 2001

Water Flea 48-hr LC50 177 mg/L OECD, 2001

Sodium 

Pentobarbital

Brown Rat* Acute oral 118 mg/kg-bw (Merck Animal Health 2014, 

Vortech Pharmaceuticals 

2015, Zoetis 2014a)

Dog Acute oral 65 mg/kg-bw (Merck Animal Health 2014, 

Vortech Pharmaceuticals 

2015)

House Mouse* Acute oral 239 mg/kg-bw (Zoetis 2014a)

* Domestic laboratory strains.

6.1 Potassium Chloride

6.1.1 Chemical Description and Product Use

Potassium chloride (KCl; CAS No. 7447-40-7; chemical structure in Appendix 3) is a salt that can 

cause cardiac arrest when administered intravenously as a saturated solution (340 grams in 1 

liter of water). Approximately 120 mL KCl is injected into the target animal (Shearer and Ramirez 

2013). WS administers KCl through intravenous or intracardiac injection after the animal is 

immobilized with an anesthetic or anesthetic sedative combination. Death usually occurs within a 

couple of minutes after injection. WS typically uses KCl to euthanize small mammals such as 

mongooses, striped skunks, raccoons, and woodchucks (Table 3a).

6.1.2 Physical and Chemical Properties

KCl, a white or colorless crystal, is odorless and has a strong saline taste. Its molecular weight is 

74.55 g/mol (NCBI 2023j). It has a boiling point of 1,500°C and a melting point of 771°C (NCBI 

2023j). It has a pH of 7 and is soluble in water (35.5 g/100 g water at 25°C) (NCBI 2023j). It has 

a low vapor pressure and is not volatile at ambient temperatures (NCBI 2023j). KCl has a 

predicted log Kow of 0.2, indicating the drug is equally partitioned between the lipid and aqueous 

phases.
EUTHANASIA AGENTS 81

6.1.3 Environmental Fate

KCl is naturally occurring in the environment, in soil, and in water (OECD 2001). KCl is soluble in 

water. In soil, KCl is fairly mobile; the type and amount of clay minerals, pH, and organic matter

affect transport and leaching (OECD 2001). Potassium is less mobile in soil than chloride, but

chloride readily bonds with potassium and leaches from the soil (OECD 2001). KCl has a low 

vapor pressure (5.73 hPa at 906°C) and is unlikely to disperse into the atmosphere due to low 

volatility (OECD 2001). The high-water solubility and low Kow suggest that KCl does not 

bioconcentrate or bioaccumulate. 

6.1.4 Metabolism

Ingested potassium is mostly absorbed by passive diffusion in the membrane of the upper 

intestine and distributed to all tissues where it plays a role in biological functions (OECD 2001). 

Potassium mediates the osmotic balance of body fluids (OECD 2001). The excretion of potassium 

is mostly in urine, with some in feces (OECD 2001).

6.1.5 Hazard Identification

KCl naturally occurs in the environment and is essential to cellular function in the body. It occurs 

in food and is used in various medical treatments. Oral toxicity is rare because large doses induce 

vomiting, and KCl is rapidly eliminated from the body (NCBI 2023j). In humans, oral overdoses of 

KCl can cause hyperkalemia (excess potassium in the blood), muscular weakness, vertigo, 

mental confusion, hypotension, and cardiovascular changes (NCBI 2023j). In one report, a 

subcutaneous injection caused skin burning and lesions, but the dose was not given (NCBI 2023j). 

Clinical signs of toxicity in animals include convulsions, exhaustion, and respiratory failure (OECD 

2001). Other signs include gastrointestinal issues, increased thirst and urine excretion, and fever 

(OECD 2001). Saturated doses of KCl impact cardiac function and can be lethal.

6.1.5.1 Acute Toxicity

KCl has low acute oral toxicity in mammals (Table 13), with an LD50 in rats of 3,020 mg/kg-bw

(OECD 2001). The physical properties of KCl make the potential for inhalation and dermal 

exposure low (OECD 2001). 

6.1.5.2 Sublethal and Chronic Toxicity

A NOAEL for KCl is 1,820 mg/kg-bw/day based on a 2-year feeding study in rats. KCl was fed to 

a group of 50 male rats at doses of 110, 450, or 1,820 mg/kg-bw/day (OECD 2001). Gastritis was 

the only treatment-related effect. In this study, KCl had no carcinogenic effects. Developmental 

effects and survival rates were not observed in offspring from pregnant mice or pregnant rats 

given up to 235 mg/kg-bw and 310 mg/kg-bw, respectively (OECD 2001). 
EUTHANASIA AGENTS 82

6.1.6 Dose-Response Assessment

6.1.6.1 Human Health Dose Response

KCl is necessary for several biological functions. In humans, the daily dietary intake for potassium 

is 50–100 mmol (2–4 g), and for chloride is 100–250 mmol (3.5–9 g) (OECD 2001). Therapeutic 

oral doses of potassium for adults are 3.0–7.5 g/day for replacement (OECD 2001). However, 

KCl at high dosages can be lethal; the oral lethal dose is estimated at 500–5,000 mg/kg-bw

(OECD 2001). A serum potassium level of 40 mg/100 mL in humans is fatal (OECD 2001). 

6.1.6.2 Ecological Dose Response

Toxicity studies have indicated that KCl is practically non-toxic to freshwater organisms. In acute 

toxicity tests, the 48-hour LC50 values for channel catfish and Daphnia magna were 720 mg/L, 

and 177 mg/L, respectively, and the 120-hour EC50 for Nitzschia linearis (algae species) was 

1,337 mg/L (OECD 2001). Table 13 summarize KCl toxicity to fish and aquatic invertebrates. KCl

is an important nutrient and constituent for terrestrial species, including mammals and birds as 

well as plants. KCl has low acute oral toxicity in mammals. Potassium is one of the three major 

nutrients for plants.

6.2 Sodium Pentobarbital

6.2.1 Chemical Description and Product Use

Sodium pentobarbital (CAS No. 57-33-0; C11H17N2NaO3; chemical structure in Appendix 3) is a 

barbiturate that rapidly depresses the central nervous system to the point of respiratory arrest 

(USDA APHIS 2019b). Intravenous injection is the most rapid and reliable technique for 

administering sodium pentobarbital. An intraperitoneal injection may be used when it would cause 

less distress than an intravenous injection (AVMA 2020). The use of chemical immobilization to 

minimize distress may precede the administration of sodium pentobarbital (USDA APHIS 2019b). 

WS typically uses sodium pentobarbital administered by intracardiac route, following anesthesia, 

as part of a 2-step method to euthanize small mammals such as striped skunks, raccoons, and 

Virginia opossums (Table 3).

Numerous euthanasia products are on the market with varying compositions of active and other 

ingredients; these products are DEA Schedule II, III, or IV controlled products. Sleepaway® 

contains 26% pentobarbital sodium, 20.7% propylene glycol, and 7.8% isopropyl alcohol (Zoetis 

2014a), while Beuthanasia®-D Special contains 39% pentobarbital sodium, 5% phenytoin sodium 

(anticonvulsant and antiarrhythmic agent and central nervous system depressant), 10–20% 

propylene glycol, and less than 10% of ethyl alcohol and benzyl alcohol (Merck Animal Health 

2014). Fatal-Plus solution contains 390 mg/mL sodium pentobarbital, 0.01 mg/mL propylene 

glycol, 0.29 mg/mL ethyl alcohol, and 0.2 mg/mL benzyl alcohol (Vortech Pharmaceuticals 2015). 

6.2.2 Physical and Chemical Properties

Sodium pentobarbital is a clear liquid mixture with color added to some formulations. For example, 

Beuthanasia-D solution is pink, and Fatal Plus is blue (Merck Animal Health 2014, Vortech 
EUTHANASIA AGENTS 83

Pharmaceuticals 2015). Many sodium pentobarbital formulations are soluble in water (Vortech 

Pharmaceuticals 2015, Zoetis 2014a). Fatal Plus solution has a pH ranging from 9.6−11.0 and a 

specific gravity of 1.105 (Vortech Pharmaceuticals 2015). Sleepaway euthanasia solution smells 

like alcohol, has a specific gravity of 1.062, and has a flash point of 39.4°C (Zoetis 2014a). Sodium 

pentobarbital is stable under normal conditions (Merck Animal Health 2014, Vortech 

Pharmaceuticals 2015, Zoetis 2014a). Hazardous decomposition products include carbon oxides 

(Merck Animal Health 2014, Vortech Pharmaceuticals 2015). 

6.2.3 Environmental Fate

Research involving euthanized animals suggests sodium pentobarbital can leach from the 

deceased animal tissue into the surrounding soil (Payne et al. 2015). The persistence of a 

pharmaceutical in soil or sediment depends upon its photostability, binding, adsorption 

capabilities, and degradation rate (Díaz-Cruz et al. 2003). Pentobarbital is not susceptible to direct 

photolysis by sunlight. Pentobarbital has an estimated soil organic carbon-water partition

coefficient (Koc) of 28 and pKa of 7.8 (NCBI 2023l). Based on the Koc value for pentobarbital, the 

drug is expected to have very high soil mobility (NCBI 2023l). The pKa value suggests 

pentobarbital will exist partially in anion form in the environment. As a result, pentobarbital is less 

likely to be absorbed by soil, which makes it more susceptible to uptake by groundwater (Saha 

2016). If pentobarbital enters surface or groundwater sources, pentobarbital is not expected to 

adsorb to suspended solids and sediment. The Henry’s Law constant for pentobarbital is 8.4x10-

13 atm-m3

/mole (NCBI 2023l). Thus, volatilization is not expected to be an important fate process 

(NCBI 2023l). One recent study examined the rate of degradation of pentobarbital in sand, topsoil, 

and potting soil over 17 weeks. At the end of the study, approximately 17% of the pentobarbital 

remained in the sand, 19% remained in the topsoil, and 10% remained in the potting soil. In sand 

and topsoil, bacterial degradation appears to be the primary mechanism for the degradation of 

pentobarbital (Bagsby et al. 2018). 

Pentobarbital was detected in groundwater samples taken from a water well located 300 meters

from a landfill in Florida approximately 15 years after the landfill received waste. Resampling 7 

years later also revealed the presence of pentobarbital (NCBI 2023l). The pKa of pentobarbital 

indicates that the drug will exist partially in the anion form if released into the environment. 

Pentobarbital is not expected to volatilize from dry soil surfaces based upon an estimated vapor 

pressure of 3.0x10-10 Hg at 25°C. It is not expected to be susceptible to direct photolysis. 

Biodegradation data is not available (NCBI 2023l). An estimated bioconcentration factor of 11 

suggests the potential for bioconcentration of pentobarbital in aquatic organisms is low (NCBI 

2023l). 

6.2.4 Metabolism

When pentobarbital is administered orally or rectally, the onset of action is 1-minute following 

intravenous administration, 10–25 minutes intramuscularly, and 15–60 minutes orally or rectally 

(NCBI 2023l). Pentobarbital is metabolized by the liver, which oxidizes the drug into more polar 

compounds such as carboxylic acid (NCBI 2023l). Between 40% and 50% of an oral dose of 
EUTHANASIA AGENTS 84

pentobarbital is excreted in urine as hydroxypentobarbital (NCBI 2023l). Plasma concentrations 

of pentobarbital decline in two phases, with a half-life of approximately 4 hours for the first phase 

and 35–50 hours for the second phase (NCBI 2023l). The plasma half-life for pentobarbital in 

adults is 15 to 50 hours and is dose-dependent (NLM 2017b).

6.2.5 Hazard Identification

In humans, relatively low doses of barbiturates depress the sensory cortex, decrease motor 

activity, and cause drowsiness. Larger doses distort judgment, suppress motor activity, reduce 

respiration, and produce sleep. Increasing the dosage further causes anesthesia. Acute overdose 

with barbiturates results in areflexia (muscles do not respond to stimuli), constriction of the pupils, 

oliguria (low urine output), tachycardia, hypotension, lowered body temperature, and coma. 

Circulatory collapse, respiratory arrest, and death could also occur in overdose situations (NCBI 

2023l). Sodium pentobarbital, in certain formulations, is regularly used as an illicit drug. The

formulations of sodium pentobarbital that WS uses are denatured and have no street value.

6.2.5.1 Acute Toxicity

Sodium pentobarbital has acute oral LD50 toxicity values of 65 mg/kg-bw in dogs, 118 mg/kg-bw

in rats, and 239 mg/kg-bw in house mice (Table 13), placing it in toxicity category II (moderately 

toxic). It is considered an eye irritant (Zoetis 2014a). Sodium pentobarbital may cause skin 

irritation after prolonged contact (time not given) and may cause temporary irritation and redness 

of the eyes on contact (Oak 2015). 

6.2.5.2 Sublethal and Chronic Toxicity

Exposure of 5 hours or longer (dose not provided) caused a loss of neuronal cells and was 

associated with cognitive learning loss and memory loss in primates (NLM 2017b). Dogs were 

dosed orally with either 50, 150, or 500 mg pentobarbital/day for eight weeks (FDA 2002). Dogs 

that received the 150 and 500 mg/day dose had statistically higher liver weights. Based on the 

study, a NOEL for pentobarbital was 50 mg/day (FDA 2002). 

In general, barbiturates are pregnancy category D drugs that have been shown to cause fetal 

damage. Barbiturates can cross the placental barrier and move throughout the fetal tissue, with 

the highest concentrations in the liver, brain, and placenta (Johnson and Sadiq 2022). 

6.2.6 Dose-Response Assessment

6.2.6.1 Human Health Dose Response

Barbiturates can be habit-forming. Daily administration of 400 mg or greater of pentobarbital for 

90 days has the potential to produce some degree of physical dependence on the drug. 

Symptoms of acute intoxication with barbiturates include unsteady gait, slurred speech, and 

involuntary eye movements. Chronic intoxication includes confusion, poor judgment, irritability, 

and insomnia. Barbiturate withdrawal can be severe and may cause death (Drugs.com 2022). 
EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION

85

Potentially lethal doses of pentobarbital are approximately 30 μg/mL (NLM 2017b). Barbiturates 

can cross the placental barrier following oral or parenteral administration. Barbiturates are also 

distributed to milk but are found at lower concentrations than those in plasma (NLM 2017b).

6.2.6.2 Ecological Dose Response

Researchers in one study injected red swamp crayfish (Procambarus clarkii) with 90.0 mg/kg-bw

sodium pentobarbital and observed behavioral changes (Winegar et al. 1988). In fathead 

minnows, sodium pentobarbital has a 96-hour LC50 of 49.5 mg/L, indicating it is slightly toxic 

(Table 13).

Animals euthanized with sodium pentobarbital are toxic to scavengers. Following several 

secondary poisoning incidents, the FDA updated its euthanasia solution regulations to state 

“euthanized animals must be properly disposed of by deep burial, incineration, or other method 

in compliance with the state and local laws to prevent consumption of carcass material by 

scavenging wildlife” in 2003 (21 CFR § 522.900 2017). Well-vascularized organs such as the liver 

have the highest concentrations of pentobarbital; subsequently, the degree of intoxication will 

depend on the amount and type of tissue ingested. Bald and golden eagles tend to move quickly 

to fresh carcasses, prefer viscera, and have a narrow tolerance for barbiturates making them 

more susceptible to secondary poisoning from pentobarbital than other species (Krueger and 

Krueger 2000). Eagle and other species deaths have been reported in at least 16 states and 

Canada as a result of scavenging on carcasses of euthanized farm animals or pet horses left in 

the field or small animal carcasses that were unburied or exposed at landfills (Krueger and 

Krueger 2000). Animals that ingest tissue contaminated with pentobarbital may become 

disoriented or comatose, and death may occur (Krueger and Krueger 2000). 

7 EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION

Determining the potential human and environmental impact of accidental or unintentional

exposure to an I&E drug involves characterizing the risk of accidental exposure to the WS 

personnel administering the drugs, the risk of an environmental release of I&E drugs, and the fate 

of these compounds when released in the environment. Risks associated with accidental 

exposure to people, nontarget animals, and the environment depend on the chemical attributes

and environmental and biological fate of the individual compound and its various formulations

summarized in this document. Acute and chronic toxicity data as well as environmental fate 

information, are summarized earlier in this document, when available, and are integrated with the 

exposure analysis to characterize the risk of I&E drugs to the public and WS personnel and to 

nontarget wildlife and domestic animals.

Environmental fate describes the processes by which I&E drugs move and are transformed in the 

environment. The environmental fate processes include 1) mobility and migration potential to 

groundwater and surface water, 2) persistence and degradation, and 3) plant uptake. Aquatic and 

terrestrial effects toxicity data for many of the I&E drugs and environmental fate data are 
EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION

86

unavailable or limited. A literature search indicates that mobility in soil data does not exist for most 

I&E drugs discussed in this HHERA. Overall, there is low potential for the environmental release 

of most I&E drugs from the proposed use pattern in this risk assessment.

7.1 I&E Drug Administration

WS uses I&E drugs in low volume. Tables 1a-d summarized the drug formulations and quantity

used, while Tables 2a-b, 3a-b, and 4a-b summarized WS animal take with different types of drugs. 

Human and nontarget species exposures to I&E drugs, and resulting risks, are mostly via

accidental exposures that can occur during the administration of the I&E drugs. 

Table 14. WS Method of I&E drug administration. 

Drug Type Drug Method of Administration

Anesthetic Ketamine HCl • Hand injection using a hand syringe or syringe 

pole

• Remote injection using darts propelled with rifles, 

pistols, or blow guns 

• Oral delivery (wearing gloves) by squirting into the 

mouth to calm an excited animal enough to allow 

injection of an additional drug (USDA APHIS 

2019b)

Anesthetic Tiletamine HCl + 

Zolazepam

• Hand injection using a hand syringe or syringe 

pole

• Remote injection using darts propelled with rifles, 

pistols, or blow guns

Sedative Azaperone, Butorphanol, 

Dexmedetomidine, 

Medetomidine HCL

• Hand injection using a hand syringe or syringe 

pole

• Remote injection using darts propelled with rifles, 

pistols, or blow guns

Sedative Midazolam • Hand injection using a syringe pole

• Remote injection using propelled darts

• Oral (for seizures; extra-label use only)

• Nasal (for seizures)

• Rectal (for seizures)

Sedative Nalbuphine • Hand injection using a hand syringe or syringe 

pole 

• Remote injection using darts as part of NalMedA

Sedative Butorphanol tartrate + 

Azaperone + 

Medetomidine (BAM)

• Hand injection using a hand syringe or syringe 

pole

• Remote injection using darts propelled with rifles, 

pistols, or blow guns

Sedative Nalbuphone + 

Azaperone + 

Medetomidine (NAM)

• Hand injection using a hand syringe or syringe 

pole

• Remote injection using darts propelled with rifles, 

Sedative Xylazine pistols, or blow guns 

Tranquilizer Acepromazine • Hand injection using a hand syringe or syringe 

pole

• Remote injection using darts propelled with rifles, 

pistols, or blow guns
EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION

87

Accessory Drug Atropine • Hand injection using a hand syringe and needle; 

For the treatment of bradycardia (low heart rate), 

intravenous injection is considered the most 

appropriate route of administration due to poor 

circulation but atropine can be given 

intramuscularly when appropriate.

Accessory Drug Doxapram • Hand intramuscular injection using a 

needle/syringe

Accessory Drug Naltrexone • Hand injection using a hand syringe and needle; 

antagonists work most rapidly when given 

intravenously but they are often given 

intramuscularly for a smoother recovery and for 

human safety concerns.(USDA APHIS 2019b)

• Oral (extra-label use only)

Accessory Drug Atipamezole, Tolazoline, 

Yohimbine HCL

• Hand injection using a hand syringe and needle; 

antagonists work most rapidly when given 

intravenously but they are often given 

intramuscularly for a smoother recovery and for 

human safety concerns.(USDA APHIS 2019b)

Accessory 

Substance

Over-the-Counter 

Antibiotics

• Applied topically by hand directly wearing latex or 

nitrile gloves

Euthanasia Agent Potassium Chloride • Only by hand using a syringe and needle, 

administered by intravenous or intracardiac 

injection (USDA APHIS 2019b)

Euthanasia Agent Sodium Pentobarbital • By hand using a syringe or syringe pole, 

administered by intravenous or intracardiac 

injection; intraperitoneal for small rodents (USDA 

APHIS 2019b)

7.2 Human Health Exposure and Risk Assessment

The exposure pathways for I&E drugs used by WS include dermal, oral, injection, and inhalation. 

This assessment focuses primarily on the environmental exposure to I&E drugs, not human 

protection and safety in the use of sharp instruments or cartridge-fired projectors. Personnel are 

advised to wear hearing and eye protection when using cartridge-fired projectors (USDA APHIS 

2019b). 

The potential for human exposure to I&E drugs is greatest for WS personnel, cooperators, or 

veterinarians who administer drugs for the WDM program. WS published the USDA-APHIS WS 

I&E Manual (USDA APHIS 2019b) to provide field personnel with information on legal 

responsibilities and policies, I&E drugs, delivery systems, administration of drugs, dosages,

handling of immobilized animals, and human safety. WS restricts the use of I&E drugs to 

individuals who complete 16 hours of training and pass an administered exam (USDA APHIS 

2019a). Certification is valid for 5 years, and continuing education is required to maintain 

certification (USDA APHIS 2019b). WS also stores I&E drugs properly and securely in an 

approved cabinet or safe or approved container and maintains accurate records for drug 

distribution and use, including proper disposal. WS avoids using remote delivery (darts) in 

populated areas (USDA APHIS 2019b). These restrictions minimize the risk of unintentionally 

exposing personnel and the public to these drugs. WS applicators have not reported any 

accidents of I&E drugs that could result in exposure to workers and the public.
EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION

88

7.2.1 Dermal Exposure

Personnel using these drugs could accidentally spray themselves with contents from drug vials 

or spill drugs while loading darts, syringes, and syringe poles. Dermal exposure may also occur 

during injection due to the animal’s sudden movements (West et al. 2007). Splashed drugs can 

be absorbed through the eyes, mucous membranes of the nose and mouth, skin, or through 

abrasions and cuts. To minimize exposure to I&E drugs, WS employees wear nitrile/vinyl/latex 

gloves and goggles or a face shield when loading and handling a syringe or dart (USDA APHIS 

2019b) and avoid the practice of recapping needles wherever possible. Accidental dermal 

exposure could still occur should personnel touch their face, skin, or other body parts with 

contaminated gloves. WS employees must also wear long-sleeved shirts or sleeve protectors and 

appropriate eye protection (USDA APHIS 2019b) during I&E activities.

7.2.2 Injection Exposure

Personnel may accidentally have a needlestick injury while handling darts, syringes, or syringe 

poles or by careless disposal of used syringes and needles. To minimize these risks, WS

employees carry darts or loaded syringes in labeled, rigid, enclosed containers and do not reuse 

needles. All used syringes and needles are placed in a biohazard sharps container for disposal, 

and empty drug vials are returned to the State Director’s office or WS National Wildlife Research 

Center (USDA APHIS 2019b). WS personnel avoid using their hand to recap a needle; instead, 

they place the cap on a wood block or piece of putty and press the needle into the cap (USDA 

APHIS 2019b). Several innovations to protect personnel are becoming more common, including 

syringes with retractable needles that “cap” the needle without recapping by hand. Although 

unlikely to occur, there is a risk of injection exposure from darts that ricochet and strike personnel.

7.2.3 Inhalation Exposure

Inhalation exposure is negligible for I&E drugs that are stored in bottles with a septum in which 

WS personnel inserts a needle to withdraw the proper dose. During mixing and loading, exposure 

through inhalation is unlikely for nonvolatile drugs. For many I&E drugs, the volatility is unknown.

Inhalation during administration also is unlikely because the drug is contained in a syringe, and 

personnel inject the drug directly into the animal or use remote darting. Inhalation could occur 

during hand injection if the syringe breaks because of the animal’s sudden movement and 

releases an aerosol of the drug (West et al. 2007). Using a syringe pole or remote darting reduces 

the risk of aerosol exposure.

7.2.4 Oral Exposure

Oral exposure through drinking water is negligible due to the WS use pattern and lack of exposure 

to water resources. Oral exposure from dietary consumption of treated animals as food sources 

is negligible for I&E drugs to the public. WS follows protocols and regulations regarding the secure 

storage, use, and disposal of I&E drugs, removing the chance the public would obtain the drugs. 

Dietary exposure of the public to I&E drugs is minimized by following recommended drug doses 
EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION

89

and complying with withdrawal periods in association with hunting seasons for game species. The

withdrawal interval recommendation for atropine given intramuscularly, intravenously, or 

subcutaneously in cattle is 28 days for meat and 6 days for milk (FARAD 2019). In black bears, 

research indicates it is safe to use Telazol (tiletamine and zolazepam) up to 15 days before 

hunting season based on 7–14-day metabolization and elimination to undetectable levels (Ryan 

et al. 2009). Table 15 presents suggested withdrawal times following intramuscular injection of 

several I&E drugs.

Most of the animal species WS treats with I&E drugs are not classified as food animals by the 

FDA (Tables 3, 4, and 5). Potential food animals released back into the environment are marked 

with an ear tag indicating they should not be used for food (USDA APHIS 2019b). The 

immobilization and accessory drugs that WS administers are in doses that are generally not toxic 

to the animal. The length of time immobilization and accessory drugs persist in a treated animal 

depends on the drug and the animal treated. Most immobilization and accessory drugs have short 

half-lives (around one to six hours) (e.g., sedatives, anesthetics, tranquilizers, most of the 

accessory drugs except for tolazoline) and rapidly metabolize in the body. Negative impacts from 

the consumption of animals treated with an immobilization and/or accessory drug by WS are

unlikely because of the safeguards WS has in place to reduce exposure (adhering to withdrawal 

periods, labeling animals that were treated) and the metabolism and excretion rate of the drug in 

the treated animal (see Table 15 for withdrawal periods). The public is unlikely to consume 

animals treated with immobilization and accessory drugs before the drugs are metabolized. 

WS personnel attempt to recover every dart that missed its intended target and spent darts that 

fall to the ground (USDA APHIS 2019b). A complete exposure pathway is not identified for surface 

water and groundwater. Small amounts of I&E drugs may be released into the soil during 

administration/application of the drug or through excretion in urine/feces; however, soil 

concentrations would be extremely low due to the low quantities of I&E drugs used by WS, the 

small amount of waste excreted and the metabolism and degradation of I&E drugs.

WS follows strict protocols when euthanizing an animal to prevent exposure to the public and 

nontarget species. WS administers a lethal potassium chloride or sodium pentobarbital injection

into the target animal through a needle and syringe, not a dart. WS personnel monitor the animal 

post-injection, remove euthanized animals from the environment, and follow the appropriate 

regulations regarding disposal. The public would not have access to these animals.

As with the public, oral exposure of WS personnel to I&E drugs is negligible. Should personnel 

eat, drink, smoke, or touch their mouths with contaminated gloves, oral exposure could occur. 

WS personnel are trained in the proper storage, handling, and disposal of I&E drugs as well as 

the post-treatment periods for target species. 
EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION

90

Table 15. Suggested withdrawal times of several immobilization and accessory drugs used in 

free-ranging wildlife and domestic livestock in North America.

Drug Withdrawal Period (Days)

Free-ranging Wildlife

Withdrawal Period (Days)

Domestic Livestock

Reference

Acepromazine 

(intramuscular)

14 7 (Cattet 2003)

Atipamezole - 14 (WAFWA 2010)

Butorphanol - 2 (as cited in (Baldridge 

et al. 2011))

Ketamine 

(intramuscular)

3 3 (Cattet 2003)

Medetomidine 

(intramuscular)

14 n/a (Cattet 2003)

Tolazoline HCl 

(intramuscular)

30 n/a (Cattet 2003)

Yohimbine 

(intramuscular)

30 7 (Cattet 2003)

Zolazepam and 

Tiletamine 

(intramuscular)

14 365 (Cattet 2003)

7.2.5 Risk Characterization of Human Health Exposures

Although the I&E drugs characterized in this risk assessment have the potential to pose a hazard 

to human health (see hazard identification and dose-response assessment sections), the potential 

for exposure of I&E drugs from WS use pattern as well as safety policy and procedures is

expected to be low resulting in minimal risks to human health. The greatest risk to human health 

is to workers who administer these drugs to immobilize or euthanize animals. The risk to these 

workers from oral, inhalation, injection, and dermal exposure is minimized by adherence to the 

proper use of personal protective equipment. In remote delivery, a small volume of the drug is 

delivered, and for some drugs, the concentration of the drug is high (West et al. 2007). Although 

some I&E drugs could be hazardous to humans at high doses, the low potential for exposure to 

these drugs suggests that adverse effects to well-trained workers will be minimal. Accidental 

exposure may occur if unprotected body parts are splashed with a drug while preparing, loading, 

or administering the drug to an animal. The exposure frequency would be low when following the 

label safety precautions. In addition, it is unlikely during an accidental exposure that an applicator 

would receive an entire dose of the drug. The WS Immobilization and Euthanasia training manual 

(WS 2019) includes instructions on human first aid in the event that an accidental exposure does 

occur.

The risk to the general public from exposure to I&E drugs from WS use is expected to be 

negligible. The lack of direct exposure and safeguards to prevent secondary exposure minimize 

the risks to the public. 

During hand injection, workers are at risk of bite wounds, kicks, and crushing injuries (West et al. 

2007). After administering immobilizing drugs, WS personnel use caution approaching the animal; 

the animal may not be fully immobilized and may respond to loud noises depending on the drug 
EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION

91

used. Personnel work quickly with the sedated animal to minimize the need to give the animal 

additional drugs to prolong sedation. 

7.3 Ecological Exposure and Risk Assessment

WS administers drugs through hand injection with a hand or syringe pole or remote darting (Table 

14). WS has no records of unintentionally injecting or darting nontarget species.

7.3.1 Aquatic Exposure Assessment

The potential for aquatic exposure to I&E drugs is minimal. The primary pathways for aquatic 

exposure during drug administration would be from darts that miss the target animal and land in 

water, spillage during the administration of a drug and subsequent runoff, or an animal that is 

drugged entering an aquatic water body and excreting that drug. These activities have a low 

probability of occurrence and suggest that exposure to potential residues would be infrequent and 

localized—WS personnel attempt to recover any darts that may miss the target animal. Aquatic 

exposure to euthanasia drugs would not occur since the administration is through direct hand

injection (not remote darting), and euthanized animals are removed and disposed of according to 

Federal, State, and local regulations. Euthanasia drugs come with a warning reminding the user 

that euthanized animals must be properly disposed of by deep burial (where allowed), 

incineration, or other authorized methods to prevent the consumption of carcasses by scavenging 

wildlife (Drugs.com 2023b). Animals that received an immobilization drug may enter water bodies 

after treatment; however, the metabolism and excretion of immobilization drugs and the low 

frequency of this type of exposure suggest a very low probability of drug exposure to aquatic 

habitats.

7.3.2 Terrestrial Exposure Assessment

WS use pattern for I&E drugs is unlikely to result in exposure to the terrestrial environment and 

nontarget terrestrial species. WS personnel administer the drugs through direct hand injection or 

remote injection. 

Exposure of nontarget terrestrial species to water or aquatic food sources contaminated with I&E 

drugs is unlikely. As discussed in the aquatic exposure section above, the exposure potential of 

water resources to I&E drugs is negligible. Therefore, dietary exposure through drinking water or 

consuming aquatic species is negligible. Secondary exposure of predators and scavengers to 

immobilizing/accessory drugs is unlikely because most drugs are used to restrain an animal 

temporarily. In the unlikely event that a predator or scavenger consumes an animal with 

detectable amounts of an immobilizing/accessory drug, the dose they would ingest is unlikely to 

be lethal. This is due to the metabolism of immobilizing/accessory drugs as well as the dose 

administered, which is a nonlethal dose in the target animal. 

WS follows Directive 2.505, Lethal Control of Animals, and Directive 2.515, Disposal of 

Carcasses, when determining the disposition of carcasses. WS personnel follow Federal, State, 
EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION

92

and local regulations regarding the disposal of animals treated with euthanasia agents. The 

immediate disposal of euthanized animals removes the risk of toxicity to scavengers. WS follows 

drug label instructions. If guidance is lacking, carcasses must be disposed of via deep burial

(where allowed), incineration, or at a landfill approved for such disposal. Subsequently, the fate 

and distribution of euthanasia drugs in the environment do not indicate a risk of secondary 

exposure.

Exposure of invertebrates and plants to I&E drugs is unlikely, given the use pattern of the drugs. 

7.3.3 Risk Characterization of Ecological Exposures

The number of animals listed as euthanized by immobilizing drugs in the WS Program can be 

misleading. Overdosing an animal with an immobilizing drug and/or accessory drug is rare as the 

doses WS administers to target animals are below the toxicity level. WS personnel likely 

immobilized the animal with the reported immobilization drug but euthanized it by different 

methods. After immobilizing an animal, WS may euthanize the animal if it is injured, for disease 

sampling, research, or if the animal was trapped at a site causing damage. For example, during 

FY11-15 (Table 2a) and FY16-20 (Appendix 2) WS reports 167 and 43 raccoons with a final 

disposition of euthanized that were immobilized under ketamine, respectively. The method of 

euthanasia was likely a method other than ketamine.

Tissue damage and irritation will occur at the site of injection. Animals immobilized through darts 

can experience localized tissue bruising or trauma caused by the energy of dart impact (West et 

al. 2007). Inaccurate placement of the dart can cause injury if it penetrates a sensitive area (West 

et al. 2007) or can administer the drug into the wrong tissue, e.g., fat tissue instead of muscular 

tissue. 

Residues of human pharmaceuticals have been widely detected in the environment, which leads 

to concerns about their potential to cause effects in nontarget species (Gunnarsson et al. 2008). 

Some of these pharmaceuticals are drugs WS administers; however, these detections were not 

from WS uses. Many aquatic species have similar target molecules to those in humans (Kostich 

and Lazorchak 2014). While large or frequent spills could have a negative impact on nontarget

species, WS infrequently uses I&E drugs, and when it does, it only uses limited quantities.

Direct and indirect risk to nontarget mammals, birds, and reptiles is expected to be negligible

based on WS use patterns for I&E drugs and lack of exposure. Similarly, the risk to aquatic 

organisms is expected to be negligible due to the lack of significant exposure. I&E drugs are not 

expected to be transported to aquatic habitats in sufficient amounts that could result in a risk to 

aquatic species.
UNCERTAINTIES AND CUMULATIVE EFFECTS

93

8 UNCERTAINTIES AND CUMULATIVE EFFECTS

The uncertainties associated with this risk evaluation arise primarily from a lack of information 

about the effects of I&E drugs, their formulations, metabolites, and potential mixtures to nontarget

organisms in the environment and the lack of environmental fate for some drugs. These 

uncertainties are not unique to this assessment but are consistent with uncertainties in human 

health and ecological risk assessments with any environmental stressor. In addition, there is 

uncertainty regarding the frequency of use and the locations where WS will use these drugs.

Another area of uncertainty is the potential for cumulative impacts on human health and the 

environment from the proposed use of I&E drugs. Areas, where cumulative impacts could occur

include co-exposure to other chemicals with a similar mode of action and exposure to other 

chemicals that could affect the toxicity of I&E drugs.

The impacts on wildlife species are expected to be negligible when put in context with other 

stressors since the drugs are used infrequently and in limited areas. Cumulative impacts on 

aquatic organisms will also be negligible because there is an extremely low probability of 

exposure to aquatic habitats from the proposed use of I&E drugs.

Cumulative impacts on human health from the use of I&E drugs are not anticipated. Human 

exposure and risk are negligible for the general public. DEA scheduled drugs require safeguards 

and security to prevent theft by the public. The probability of exposure is greatest for workers 

involved with administering these drugs. However, the risk to this group will be negligible based 

on the low risk of exposure to I&E drugs when following applicable safety protocols, including 

wearing the appropriate personal protective equipment. There is potential for exposure to other 

chemicals used during wildlife management; however, the use of personal protective equipment 

reduces the potential for cumulative impacts related to exposure to numerous chemicals. WS

does not anticipate cumulative risk to the public from exposure to multiple chemicals because of 

the methods of application and program controls, which include marking animals that people may 

want to harvest to indicate the animal was treated with an immobilization/accessory drug. 
SUMMARY 94

9 SUMMARY

WS use patterns, protocols, and label instructions for I&E drugs minimize the direct and indirect 

risks to the public and WS applicators. Exposure and risk to terrestrial and aquatic nontarget

organisms are also negligible for all I&E drugs WS uses.

10 PREPARERS: WRITERS, EDITORS, AND REVIEWERS

10.1 Writers for “Use of Immobilization and Euthanasia Drugs in Wildlife Damage 

Management Risk Assessment”

Primary Writer: Andrea Lemay 

Position: USDA-APHIS-Policy and Program Development (PPD), Environmental and Risk 

Analysis Services (ERAS), Biological Scientist

Education: B.S. Plant and Soil Science (Biotechnology) - University of Massachusetts; M.S. 

Plant Pathology - North Carolina State University 

Experience: Fifteen years of service in APHIS conducting risk analysis. Seven years of 

experience in preparing environmental analyses in compliance with the National 

Environmental Policy Act.

Primary Writer: Michael McCaskill

Position: USDA-APHIS-Policy and Program Development (PPD), Environmental and Risk 

Analysis Services (ERAS), Toxicologist, New Market, MD

Education: B.S. Environmental Science – University of Florida; MPH Industrial HygieneUniversity of South Carolina, Ph.D. Toxicology-Florida Agriculture and Mechanical University

Experience: Ten years of experience conducting human toxicological research at Florida 

Agriculture and Mechanical University, University of Nebraska Medical Center, and Tulane 

University. Four years of experience conducting human health and environmental 

toxicological risk assessments and assisting environmental compliance programs at the 

Florida Department of Health, Commonwealth of Pennsylvania, and USDA.

Writer: Thomas C. Hall

Position: USDA-APHIS-WS, Operational Support Staff, Staff Wildlife Biologist, Fort Collins, CO

Education: BS Biology (Natural History) and BA Psychology – Fort Lewis College; MS Wildlife 

Ecology – Oklahoma State University

Experience: Special expertise in wildlife biology, identification, ecology, and damage 

management. Thirty-seven years of service in APHIS Wildlife Services, including operations 

and research in CO for research and OR, GU, CA, OK, and NV for operations conducting a 

wide variety of programs, including bird damage research and management, livestock 

protection (predators and birds), invasive species management, wildlife hazard management 

at airports, property and natural resource protection including waterfowl, brown tree snake, 

feral swine, rodent, and beaver damage management. Researched, applied, and supervised 

the use of 4-AP. 

Writer: Jim Warren 

Position: USDA-APHIS-Policy and Program Development (PPD), Environmental and Risk 

Analysis Services (ERAS), Environmental Toxicologist, Little Rock, AR 

Education: B.S. Forest Ecology and M.S. Entomology – University of Missouri; Ph.D. 

Environmental Toxicology – Clemson University
PREPARERS: WRITERS, EDITORS, AND REVIEWERS

95

Experience: Sixteen years of experience working for APHIS preparing ecological risk 

assessments and providing assistance on environmental compliance. Prior experience 

before joining APHIS includes other government and private sector work regarding 

ecological risk assessments related to various environmental regulations.

Editors/Contributors for “Use of Immobilization and Euthanasia Drugs in Wildlife Damage 

Management Risk Assessment”

Editor/Contributer: Shelagh DeLiberto 

Position: USDA-APHIS-Wildlife Services (WS), Operational Support Staff, Environmental 

Coordinator, Fort Collins, CO

Education: BA Biology and Environmental Science – Ithaca College; MS Wildlife Biology –

Colorado State University 

Experience: Twenty years of service in APHIS conducting wildlife research. Two years of 

experience in preparing categorical exclusions and environmental analyses in compliance 

with the National Environmental Policy Act.

Editor/Contributor: Emily Ruell 

Position: USDA-APHIS-WS, NWRC, Registration Specialist, Fort Collins, CO

Education: B.S. Zoology and Biological Aspects of Conservation – University of Wisconsin -

Madison; M.S. Ecology – Colorado State University (CSU); M.A. Political Science – CSU

Experience: Nine years of experience with WS NWRC preparing and reviewing vertebrate 

pesticide registration data submissions and other registration materials and providing 

pesticide regulatory guidance to WS, WS NWRC, and collaborators. Prior experience before 

joining APHIS includes seven years of conducting field and laboratory wildlife research at 

CSU and environmental policy research for the U.S. Geological Survey.

10.2 Internal Reviewers

USDA APHIS Wildlife Services

Reviewer: Are R. Berentsen

Position: USDA-APHIS-WS, Biologist

Education: BS in Zoology, University of California at Davis, MS Wildlife Biology, Utah State 

University

Experience: Biologist/wildlife biologist at NWRC for 17 years. Prior experience, 10 years wildlife 

research at Utah State University, University of California

Reviewer: Anthony G. Duffiney 

Position: USDA-APHIS-WS, State Director, Okemos, MI 

Education: BS Fisheries and Wildlife Biology, Michigan State University 

Experience: Twenty-five years of service with APHIS Wildlife Services in Michigan, Florida and 

West Virginia. Specialized experience in all levels of WS Operations including pesticide use, 

NEPA, FOIA, ESA, predator control, feral swine damage management, wildlife hazards at 

airports, wildlife disease sampling, invasive reptiles, urban wildlife damage. Worked with 

NWRC and a private livestock feed company in developing new baiting strategy for use of 

DRC-1339 in cattle feedlots and dairy farms. Conducted bait trials with traditional baits to 

prove efficacy of new bait material, CU Bird Carrier. Trained WS personnel from 10 State 

programs in use of new bait. Experience with DRC-1339 to control damage caused by 
PREPARERS: WRITERS, EDITORS, AND REVIEWERS

96

European starlings, common and boat-tailed grackles, rock pigeons, American crows, 

common ravens, and ring-billed gulls.

Reviewer: John Forbes

Position: State Director, West Virginia

Education: BS Wildlife Resources, West Virginia University; MS Wildlife Ecology, Mississippi 

State University

Experience: Twenty three years of field experience using immobilization and euthanasia drugs; 

served on WS I&E committee since 2009; 16 years as a WS State Director in two states.

Reviewer: (John) Tyler Genders

Position: USDA-APHIS-WS, Wildlife Disease Biologist

Education: BS in Wildlife Management, The Ohio State University 

Experience: 12 years of service in wildlife damage management with APHIS Wildlife Services. 

Expertise in wildlife damage management, wildlife diseases, and emergency disease 

outbreaks. 

Reviewer: Amy T. Gilbert 

Position: USDA APHIS WS NWRC, Research Biologist

Education: BA Biology – Boston University, PhD Ecology and Evolutionary Biology – University 

of Tennessee

Experience: Ten years of service with WS NWRC using immobilization and euthanasia drugs for 

WDM research.

Reviewer: Steve Greiner

Position: USDA-APHIS-Wildlife Services, Safety and Occupational Health Manager, Fort Collins, 

CO

Education: BA Environmental Biology – University of Colorado

Experience: Thirty five years of service with APHIS Wildlife Services. Certified Occupational 

Health and Safety Technologist through the joint Board of Certified Industrial Hygienists and 

Certified Safety Professionals since 1996. National Rifle Association Certified Instructor since 

2007. Special expertise in occupational, chemical, biological, and radiological safety and 

health, environmental management, hazardous waste disposal, hazardous materials 

shipping, emergency response, workers compensation, and animal welfare regulations.

Reviewer: Chad M Heuser

Position: USDA-APHIS-WS, State Director, UT

Education: BS Degree in Fisheries and Wildlife Biology, Utah State University

Experience: Twenty-four years of service with APHIS Wildlife Services in Utah, Washington 

and Arizona. Specialized experience in all levels of WS Operations including pesticide use, 

NEPA, FOIA, ESA, predator control, feral swine damage management, wildlife hazards at 

airports, wildlife disease sampling, natural resource protection, rabies program and urban 

wildlife damage management. I have provided pesticide safe handling and use to 

numerous WS employees over the years.
PREPARERS: WRITERS, EDITORS, AND REVIEWERS

97

Reviewer: Daniel Hirchert

Position: USDA-APHIS-WS, State Director, Sun Prairie, WI

Education: BS in Field Biology, University of Wisconsin

Experience: Twenty-eight years of service in wildlife damage management with APHIS Wildlife 

Services and the Wisconsin Department of Natural Resources. Expertise in agricultural crop 

damage, aviation safety, urban wildlife conflicts, and natural resource protection.

Reviewer: Shylo R. Johnson 

Position: USDA APHIS WS NWRC, Biologist

Education: BS Biology – College of Idaho, MS Animal Behaviour and Welfare – University of 

Edinburgh

Experience: Seventeen years of service with NWRC using immobilization and euthanasia drugs

Reviewer: Michael McBride

Position: Attending Veterinarian, APHIS, Wildlife Services

Education: Doctor of Veterinary Medicine – Louisiana State University

Experience: I was a zoo veterinarian for 16 years prior to joining APHIS. During this time, I 

anesthetized and immobilized thousands of animals and dozens of different species. I am 

very familiar with all the drugs spoken about in the document. Since joining APHIS, I have 

become an I&E instructor to provide anesthesia instruction to WS staff. I also serve on the

WS I&E Sub-committee.

Reviewer: Daniel Morgan

Position: USDA -APHIS-WS, Wildlife Biologist, Potsdam NY

Education: BS in Environmental Science, SUNY Environmental Science and Forestry

Experience: 22 years of service in wildlife damage management with APHIS Wildlife Services. 

Expertise in immobilizing rabies vector carnivores as part of the National Rabies 

Management Program

Reviewer: Dave Ruid

Position: USDA-APHIS-WS, District Supervisor, Rhinelander, WI (Member of the WS I/E 

Committee)

Education: BS in Forestry/Wildlife Management, LA Tech University; MS in Wildlife 

Management, Utah State University

Experience: 32 years of service in wildlife damage management with APHIS Wildlife 

Services. Expertise in wildlife damage management and immobilization of Federally 

Endangered large carnivores. 

Reviewer: Caleb Wellman

Position: USDA-APHIS-WS, Staff Wildlife Biologist, Sandusky, OH

Education: BS in Fish and Wildlife Management, The Ohio State University

Experience: 19 years of service in wildlife damage management with Wildlife Services, 

including 10 years with a focus on the immobilization of mesocarnivores.
PREPARERS: WRITERS, EDITORS, AND REVIEWERS

98

10.3 Peer Review

The Office of Management and Budget requires agencies to have peer review guidelines for 

scientific documents. The APHIS guidelines were followed to have "Use of Immobilization and 

Euthanasia Drugs in Wildlife Damage Management" peer reviewed. WS worked with the 

Association of Fish and Wildlife Agencies to have experts review the documents.

10.3.1 Peer Reviewers Selected by the Association of Fish and Wildlife Agencies

Colorado Parks and Wildlife

Arizona Game and Fish Department

Wisconsin Department of Natural Resources

10.3.2 Comments

1. All game species should be tagged/marked whenever drugs are used. Add to Executive 

summary.

Response: WS follows the guidance in our Immobilization and Euthanasia manual based 

upon the Animal Medical Drug Use Clarification Act (AMDUCA). The manual states that 

personnel will not chemically immobilize food animals, as defined by the State, within a 

specified withdrawal period before or during a harvest season unless the animal is visually 

tagged, held in quarantine for the specified period, or euthanized. Therefore, all game 

species must be marked within the specified period if they are not held or euthanized, but 

not whenever drugs are used. We have added language to the Executive Summary to 

clarify this procedure.

2. Section 1.2: Some syringe poles have a spring-loaded or CO2-charged trigger, not all.

Response: We have changed the wording of the paragraph on syringe poles to clarify 

that not all syringe poles have a spring-loaded or CO2-charged trigger.

3. KCL should only be used in anesthetized animals. According to the text which indicates 

that only one method of take can be provided and if another IE drug was used it should 

have prevented KCl being indicated. KCl should never be used without a general 

anesthetic.

Response: WS only uses potassium chloride in animals that have been anesthetized. We 

have verified this by checking individual work tasks associated with potassium chloride. 

Every animal euthanized with potassium chloride was anesthetized first.

4. Section 2.1.4 Johnson et al. (2023b) study discussing ketamine residues in raccoons postimmobilization. What was the result of this study?

Response: We have included the Johnson et al. (2023b) study results, which detected 

ketamine in tissue samples on days 2 and 6 post-immobilization.

5. Section 3.1.5.1 Do the authors mean panting instead of sweating in reference to a reaction 

to intramuscular and intravenous injections of Azaperone?
PREPARERS: WRITERS, EDITORS, AND REVIEWERS

99

Response: The study's authors referenced in this section (Pitman-Moore 1982) 

specifically indicate increased sweating. We are repeating the original authors' direct 

statement in this section.

6. Reviewer suggests including the phrase “with an anesthetic or anesthetic sedative 

combination.” After this sentence in Section 6.1.1 “WS administers KCl through 

intravenous or intracardiac injection after the animal is immobilized.”

Response: We have edited this section of text to include the phrase “with an anesthetic 

or anesthetic sedative combination.

7. Executive summary “It is rare for a well-trained applicator” to miss their target during 

remote darting” Reviewer states: This seems inaccurate; however, I may be unfamiliar 

with WS darting practices. Remote darting of free-ranging wildlife is inherently challenging. 

In my experience, missing a free-ranging animal target is actually not uncommon for 

experienced individuals conducting remote darting and extremely common during 

helicopter darting operations. Animals may move at just the wrong moment or a wind gust 

might catch your dart. However, if WS personnel are primarily darting in highly controlled 

situations, perhaps this is not the case.

Response: Remote darting of free-ranging wildlife can be challenging. However, WS does 

not often dart wildlife from helicopters and more regularly darts free-ranging wildlife in 

more controlled situations.

8. Section 2.1.1 “Concentrated ketamine can be purchased with a veterinary prescription.” 

All forms of ketamine used in wildlife require veterinary prescription/oversight - so this 

seems like an odd statement. Perhaps what would be more appropriate would be to say 

concentrated ketamine can be purchased through a compounding pharmacy?

Response: We have edited this statement for clarity. All forms of ketamine do require 

veterinary prescription oversight. We have included in this statement that concentrated 

ketamine can be purchased with a veterinary prescription through a compounding 

pharmacy.

9. Section 2.2.2 It might be worth also adding that Telazol is sold in a vial containing a 1:1 

ratio of tiletamine to zolazepam. This will help to make the later discussions on mg/kg 

dosing more clear since both drugs are at the same concentration in this mixture.

Response: We have included the 1:1 ratio information in this statement for clarity.

10. Section 2.2.6.2 This is where it would be helpful to make sure it is understood that 

Tiletamine and zolazepam are at the same concentration in the vial. Otherwise, it might 

be unclear whether you are referring to just tiletamine or just zolazepam with this dosing 

information.

Response: We agree that adding the ratio of tiletamine to zolazepam in Section 2.2.2 

makes it more clear that the drugs are at the same concentration in the vial.
PREPARERS: WRITERS, EDITORS, AND REVIEWERS

100

11. Section 3.4.1: There seems to be some confusion between what requires a prescription 

versus what is acquired through a compounding pharmacy. Nearly all immobilization 

drugs administered to wildlife require a veterinary prescription. Some drugs have to be 

specifically compounded into formulations with high concentration to facilitate appropriate 

wildlife dosing in small volumes.

Response: We have edited this sentence to include that the medetomidine HCL is a 

concentrated form and is being purchased through a compounding pharmacy.

12. Section 3.6.1 To my knowledge - most nalbuphine used for wildlife immobilization will 

actually be purchased through a compounding pharmacy and not purchased in the 

commercially available concentrations.

Response: We understand that Nalbuphine HCL may be purchased from compounding 

pharmacies for use with Azaperone and Medetomidine HCL. This section describes 

Nalbuphine HCL alone, and the statement about concentrations available is accurate.

13. Section 3.8.1 “Non-veterinarians may administer NAM without encountering record- and 

safe-keeping requirements (Wolfe et al. 2016a).” May want to clarify this statement that 

non-veterinarians my administer NAM with a veterinary prescription without encountering 

DEA record and safe keeping requirements. A valid veterinary client-patient relationship 

is required under AMDUCA and there could still be record keeping requirements from the 

prescribing veterinarian to ensure that legally required relationship is valid.

Response: We have deleted this statement from the section. Record-keeping 

requirements are covered in another section. 

14. Section 3.8.1: “In a study evaluating the use of NAM raccoon immobilization, NAM came 

formulated with 40 mg/mL nalbuphine, 10 mg/mL azaperone, and 10 mg/mL 

medetomidine (Johnson et al. 2023a). This is the formulation listed in the NalMed-A 

patent. Seems odd to cite it under this publication when multiple publications have used 

this formulation and the 2016 patent describes this formulation?

Response: We have cited Johnson et al. 2023a here because we reference the study 

done by our WS NWRC staff utilizing the drug combination. We have cited the 2016 patent 

and other studies throughout this section. 

15. Table 14. Atipamezole, and Atropine: This might benefit from revision to differentiate 

between recommendations for atropine vs atipamezole. Uncertain of USDA WS 

protocols, but we have seen adverse reactions to full doses (and even 50% doses) of 

atipamezole given intravenously (tremors, ataxia, head-pressing) and zoopharm has 

reported issues with renarcotization when full dose of atipamezole is given intravenously. 

Recommendation should be to give most of atipamezole intramuscularly and likely no 

more than 33% of the dose should go IV.

Response: We have edited Table 14 to account for the potential hazard to human safety 

with an intravenous injection for all alpha-antagonists. We have also changed the atropine 

method of administration to correctly identify its use.
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101

16. I assume unrecovered darts, if any, would be documented? Any statistics at hand to back 

up success of dart recovery?

Response: WS Immobilization and Euthanasia manual instructs employees to recover 

every dart/missed dart used. Therefore WS does not track dart recovery. 

17. Executive summary: “WS follows withdrawl periods and often tags animals...” "often tags" 

could be open for interpretation or misinterpretation. Would it be more appropriate to say 

something like "tags according to x,y,z guidelines" etc.

Response: WS follows the guidance in our Immobilization and Euthanasia manual based 

upon the Animal Medical Drug Use Clarification Act (AMDUCA). The manual states that 

personnel will not chemically immobilize food animals, as defined by the State, within a 

specified withdrawal period before or during a harvest season unless the animal is: visually 

tagged, held in quarantine for the specified period, or euthanized. Therefore, all game 

species must be marked within the specified period if they are not held or euthanized, but 

not whenever drugs are used. We have added language to the Executive Summary to 

clarify this procedure.

18. Section 7.2.5 Is it worth mentioning/enforcing that training/protocols cover accidental 

exposure? I.e. if it were to happen, staff are prepared to know what to do?

Response: It is worth mentioning that training/protocols cover accidental exposure. We 

have edited this section to include references to the WS Immobilization and Euthanasia 

training manual, which covers steps to take in case of accidental exposure. These include 

maintaining field copies of SDS and/or labels, notifying local hospitals before conducting 

operations, noting the time of exposure, and transporting the exposed person to a local 

emergency clinic.

19. Is there consideration for updating the database so that this information can be accurately 

summarized? I don't know if that is important long-term or not, but would possibly prevent 

future misinterpretation of the data.

Response: The database that is used to summarize WS operational data is being updated

to a new system. It is possible that irregularities such as only being able to list a single 

method of take with an animal will be resolved in the tracking software. 

20. Table 14. Tolazoline, yohimbine HCl: The one area where a risk might need to be 

addressed is in the statements that drug antagonists are “most effective when given 

intravenously. Full intravenous administration of some drug antagonists can create a 

hazard for human safety as animals may have rapid recoveries that do not allow sufficient 

time for humans to move to a safe distance from the recovering animal. They can also 

pose a hazard to the animals with certain drug combinations that may result in difficult 

recoveries or renarcotization when antagonists are given intravenously. I would suggest 

revising this to either specify what is meant by “most effective” to ensure that is not 

confused with the recommendation for route of administration or to specify the 

recommended route of administration or simply list available routes of administration.
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102

Response: We have edited Table 14 to account for the potential hazard to human safety 

with an intravenous injection for all alpha-antagonists.

Comments received not requiring a response.

1. Overall, I found the document very thorough and detailed. From the perspective of a 

state wildlife manager, I found no significant questions or concerns and think that 

potential risks were adequately considered and addressed. Specifically, I found all 

portions of the assessment to be thorough and complete. I also found mitigation 

recommendations/actions as described to minimize adverse impacts were well-reasoned 

and defensible.

2. Document is complete and of good quality. Standard operating procedures described in 

the document will minimize or mitigate the risk to human, animal, and environmental 

health. Descriptions of hazards and risks are accurate and complete. Assumptions and 

uncertainties are clearly stated. References appear appropriate.

3. This document is thorough and describes the various immobilization and euthanasia 

drugs accurately and in sufficient detail without overly in-depth literature reviews for each 

substance.

4. Hazards are appropriately identified and addressed in the document.
APPENDIX 1. Over-the-Counter Antibiotics 103

APPENDIX 1. Over-the-Counter Antibiotics

A1.1 Chemical Description and Product Use

Over-the-counter topical antibiotics such as Neosporin® are applied to skin abrasions and cuts to 

prevent post-capture infections. These topical antibiotics are used infrequently in small quantities. 

Most topical antibiotics contain one or a combination of the following anti-infective components: 

polymyxin B sulfate, neomycin sulfate, and bacitracin zinc (GlaxoSmithKline 2013). Polymyxin B 

sulfate and neomycin sulfate act against the following microorganisms: Staphylococcus aureus, 

Escherichia coli, Haemophilus influenza, Klebsiella-Enterobacter species, Neisseria species, and 

Pseudomonas aeruginosa. Bacitracin is active against most Gram-positive bacteria, Neisseria

spp., and Haemophilus influenza (GlaxoSmithKline 2013). WS uses antibiotics to treat minor skin 

abrasions or cuts in wildlife prior to releasing the animal.

A1.2 Physical and Chemical Properties

Topical antibiotic ointments are typically a clear, pale yellow, or white gel composed of substances 

such as polymyxin B sulfate, neomycin sulfate, or bacitracin zinc (GlaxoSmithKline 2013, Johnson 

and Johnson 2009, Pfizer 2000). One common antibiotic ointment, Neosporin, is slightly soluble 

in water but a stable product (Pfizer 2000).

A1.3 Environmental Fate

Environmental fate of topical antibiotics is not available.

A1.4 Metabolism

Antibiotic ointments are applied topically to the skin. Systemic absorption of bacitracin, neomycin, 

and polymyxin B is negligible, except when applied to large areas or extended periods. Polymyxin 

B has a high affinity for cell membranes, so there is little systemic absorption when applied to 

open wounds. Bacitracin and neomycin could be absorbed systemically if applied to damaged 

skin. If systemic absorption does occur, bacitracin and neomycin are excreted renally (PDR 2018). 

Approximately 10−40% of the bacitracin is excreted within 24 hours. The elimination half-life of 

bacitracin is 1.5 hours (NCBI 2023x).

A1.5 Hazard Identification

Humans started using triple antibiotic ointments containing neomycin, polymyxin B, and bacitracin 

as prescription products in the 1950s. Triple antibiotic ointments have been available over the 

counter since the 1970s (Jones et al. 2006). If used in large quantities or in large areas for 

prolonged periods of time, neomycin sulfate can cause toxicity; neomycin sulfate, polymyxin B 

sulfate, and bacitracin zinc can cause nephrotoxicity; and polymyxin B sulfate can cause 

neurotoxicity (GlaxoSmithKline 2013). Some individuals have reported allergic sensitization after 

using antibiotic ointments. In one clinical study, neomycin-induced allergic skin reactions occurred 
APPENDIX 1. Over-the-Counter Antibiotics 104

in 0.09% of individuals, while another study reported the incidence at approximately 1% 

(GlaxoSmithKline 2013). Increased absorption in very young children is also possible; therefore, 

products such as Neosporin are not recommended for use in children under two years 

(GlaxoSmithKline 2013). 

A1.5.1 Acute Toxicity

The acute oral LD50 of bacitracin zinc is 2,000 mg/kg in guinea pigs and greater than 3,750 mg/kg 

in house mice. The acute oral LD50 of bacitracin zinc, neomycin sulfate, and polymyxin B sulfate 

in house mice is >3,750 mg/kg, 8,000 mg/kg, and 750 mg/kg, respectively (Table A3-1). 

Table A1-1. Acute toxicity values for over-the-counter antibiotics.

Chemical Test Species Test Type LD50 Reference

Bacitracin zinc House Mouse* intravenous 360 mg/kg (Akorn Animal Health 2015)

Bacitracin zinc Brown Rat* Intraperitoneal 190 mg/kg (Akorn Animal Health 2015)

Bacitracin zinc House Mouse* Intraperitoneal 300 mg/kg (Akorn Animal Health 2015)

Bacitracin zinc House Mouse* Acute oral >3,750 mg/kg (Akorn Animal Health 2015)

Bacitracin zinc Guinea pig Acute oral 2,000 mg/kg (Akorn Animal Health 2015)

Bacitracin zinc Japanese Quail Acute oral >316 mg/kg (Akorn Animal Health 2015)

Neomycin sulfate House Mouse* Acute oral 8,000 mg/kg (Akorn Animal Health 2015)

Neomycin sulfate House Mouse* Intravenous 17,400 mg/kg (Akorn Animal Health 2015)

Neomycin sulfate House Mouse* Intraperitoneal 305 mg/kg (Akorn Animal Health 2015)

Polymyxin B sulfate House Mouse* Acute oral 750-790 mg/kg (Akorn Animal Health 2015, 

Pfizer 2000)

Polymyxin B sulfate House Mouse* Intravenous 5,400 μg/kg (Akorn Animal Health 2015)

Polymyxin B sulfate House Mouse* Intraperitoneal 20,500 μg/kg (Akorn Animal Health 2015)

* Domestic laboratory strains.

A1.5.2 Sublethal and Chronic Toxicity

The LDLo of polymyxin B sulfate given to dogs intravenously was reported to be 8 mg/kg (Akorn 

Animal Health 2015). 

A1.6 Dose-Response Assessment

A1.6.1 Human Health Dose Response

In humans, topical antibiotic ointments may cause allergic contact dermatitis (NCBI 2023x). 

Polymyxin B is toxic to kidneys and the nervous system and hazardous if inhaled or ingested 

(Sciencelab 2013). On the other hand, Neomycin sulfate has a low absorption rate even if 

ingested; approximately 97% of the drug is eliminated unchanged in the feces. Prolonged 

consumption of oral neomycin sulfate tablets could result in systemic drug levels that are high

enough to produce neurotoxicity, ototoxicity (toxic to the ear), and nephrotoxicity (NLM 2017c). 

Dermal absorption of bacitracin ointment is negligible. Intramuscular injection of bacitracin is 

widely distributed in the body (NCBI 2023x). Nephrotoxicity occurred when 200,000 units of 
APPENDIX 1. Over-the-Counter Antibiotics 105

bacitracin were given parenterally for several days, while oral doses of up to 240,000 units caused 

virtually no side effects or absorption (NCBI 2023x). 

A1.6.2 Ecological Dose Response

We are unable to find information on the ecological dose response for over-the-counter antibiotics.
APPENDIX 2. FY16-20 Data Tables 106

APPENDIX 2. FY16-20 Data Tables

Table A2-1a. The annual average number of animals immobilized with ketamine, with or without 

xylazine, by WS in WDM activities from FY16 to FY20 throughout the United States and the final 

disposition of the animal (euthanized or freed). To standardize the data for the table, drugs tracked 

in cubic centimeters were converted to mg of drug used.

Species Euthanized Freed Ketamine (mg) Xylazine (mg)

Gray Wolf 0.2 29 10,214 2,021

Gray Fox 0 8 458 92

Black Bear 1 25 12,308 3,098

Raccoon 43 4,159 250,128 49,928

Striped Skunk 38 157 10,163 2,033

Virginia Opossum* 3 5 1,033 207

Red Fox 0.4 5 290 58

Other Predators (11 spp.)1 0.2 14 2,866 515

Wild Turkey 0.8 2.4 1,166 294

White-tailed Deer 0 6.6 2,382 1,016

Mule 0 0.2 0 20

Total (19 spp.)3 87 4,405 291,008 59,282

* - Introduced populations Other predator = badger, beaver, bobcat, coyote, domestic dog, feral/free-roaming dog,

fisher, mountain lion, mink, porcupine, and river otter 1 Other predator species include domestic dogs, and feral/freeranging dog, subspecies of the wolf, and thus, not included in the total species count. 

Table A2-1b. The annual average number of animals immobilized with tiletamine-zolazepam, with 

or without xylazine, by WS in WDM activities from FY16 to FY20 throughout the United States 

and the final disposition of the animal (euthanized or freed). To standardize the data for the table, 

drugs tracked in cubic centimeters were converted to mg of drug used.

Species Euthanized Freed TiletamineZolazepam (mg) Xylazine (mg)

Gray Wolf 0 9 5,900 0

Black Bear2 0.2 5 2,650 0

- Louisiana Black BearT&E 1 0.2 12 6,703 0

Grizzly BearT&E 0 0.6 1,300 0

Other Predators (6 spp.)2 2 7 1,246 0

Feral Swine 0 10 2,596 1,100

Other Ungulates (3 spp.) 0 4 1,054 710

Total (15 spp.) 2.6 50.6 21,449 1,810

Other predator = bobcat, dog*, mountain lion, raccoon, Virginia opossum, and striped skunk; Other ungulate = mule 

deer, white-tailed deer, moose. 1 T&E = Federally listed threatened and endangered species – the Louisiana black bear 

is no longer listed but included. 2 Other predator species include domestic dogs, a subspecies of the wolf, and thus, not 

included in the total species count. 

Table A2-1c. The annual average number of animals immobilized with nalbuphine, azaperone, 

and medetomidine (NAM) by WS in WDM activities from FY16 to FY20 throughout the United 

States and the final disposition of the animal (euthanized or freed). To standardize the data for 

the table, drugs tracked in cubic centimeters were converted to mg of drug used.

Species Euthanized Freed Nalbuphine-Azaperone-Medetomidine (cc)

Raccoon 2.6 15.6 5.7

Striped Skunk 15.4 5.8 5.5
APPENDIX 2. FY16-20 Data Tables 107

Coyote 0.8 0.2 2.5

Feral/free-ranging Cat 0.8 1.8 1.2

Other Predator (4 spp.) 0.2 2.2 1.7

Total (8 spp.) 19.8 25.6 16.6

Other predator = Gray wolf, mountain lion, Virginia opossum, and porcupine.

Table A2-2a. The annual average number of animals euthanized with potassium chloride by WS 

in WDM activities from FY16 to FY20 throughout the United States.

Species Euthanized Potassium Chloride (KCl) (cc)

Raccoon 19.2 70.6

Striped Skunk 11 44.3

Feral/Free-roaming Cat 2.4 6.8

Louisiana Black BearT&E 2 0.2 12

Total 32.8 133.7

Table A2-2b. The annual average number of animals euthanized with sodium pentobarbital (390 

mg/ml) and Fatal Plus solution by WS in WDM activities from FY16 to FY20 throughout the United 

States.

Species Euthanized Sodium Pentobarbital

(sodium pentobarbital (390mg/mL) and Fatal 

Plus) Striped Skunk 1,580 3,144

Raccoon 164 55

Virginia Opossum* 87 134

Common Gray Fox 8 21.6

Other Predator (6 6.8 21.3

Fox Squirrel 2.2 2.2

Mule Deer 0.6 3.4

Total 1848.6 3,381.5

* - Introduced populations; Other predator –bobcat, coyote, red fox**, black bear, feral/free-roaming cat, 

mink

Table A2-3a. The annual average number of animals recovered with the alpha-2 antagonist drug

Atipamezole by WS in WDM activities from FY11 to FY15 throughout the United States.

Species Freed Atipamezole (5 and 25 mg/mL; cc)

Gray Wolf 8.8 67.8

Coyote 1 16.6

Other Predator (4 Sp.) 14 62

White-tailed Deer 0.2 0.55

Total 24 147

* Introduced Species Other predator –black bear, feral/free-roaming cat, Mountain lion, raccoon

Table A2-3b. The annual average number of animals recovered with the alpha-2 antagonist drug

Tolazoline by WS in WDM activities from FY11 to FY15 throughout the United States.

Species Freed Tolazoline (100mg/mL; cc) 

Feral Swine* 7.2 1,912

Mountain Lion 0.8 160

Mule Deer 1.4 400
APPENDIX 2. FY16-20 Data Tables 108

White-tailed Deer 0.4 36

Total 9.8 2,508

Table A2-3c. The annual average number of animals recovered with the alpha-2 antagonist drug

Yohimbine by WS in WDM activities from FY11 to FY15 throughout the United States.

Species Freed Yohimbine (2 mg/mL; cc)

Gray Wolf 10.6 44

Total 10.6 44

 
APPENDIX 2. FY16-20 Data Tables 109

Table A2-4. States where WS used wildlife drugs for FY16–FY20. 

State Ketamine 

(mg)

Tiletamine

-Zolazepam

(mg)

Xylazine 

(mg)

NAM 

(cc)

Alpha2

Antag. (cc)

Euthanasia 

(cc)

AL 17,073 - 3,410 - - -

AZ - 74 - - - -

CA 1,402 3,292 1,976 - 2,618 2,931

GA 7,026 - 1,392 - - -

ID - 4,830 - - - -

IL - 174 92 - 36 -

KS - 2.1 80 - - 5.2

KY 675 - 135 - - 1.8

LA - 6,843 - - - 12

MA 11,257 - 2,251 - - -

MD 6,560 - 1,304 - -

ME 19,839 - 3,535 - - 15.5

MI 1,078 - 208 - 2.8 -

MN 5,628 - 866 - 0.84 -

MT - 4,901 - - - -

NC 13,604 348 2,686 - - -

ND - - - - 0.6

NE - - - - - 256

NJ 3,335 - 1,211 - .02 -

NM 180 - 420 - - -

NY 24,731 - 4,946 - - -

OH 41,517 - 8,303 - - 1

OR - 170 - - - 2.4

PA 13,428 - 2,686 - - 0.2

TN 16,473 - 3,235 - - 11.6

TX 917 - 183 - - 23.4

UT 200 - 40 - - 237

VA 27,602 - 5,520 - - 0.4

VT 45,701 620 9,140 - - -

WA - 40 - - - 2.4

WI 14,273 - 2,807 - 107.3 7.6

WV 18,293 - 3,659 - - -

WY 2,330 520 466 16.6 29.9 117

Total 293,122 21,814 60,551 16.6 2,794.9 3,625.1

States 23 12 25 1 7 17
APPENDIX 3. Chemical Structures. 110

APPENDIX 3. Chemical Structures. 

Source: PubChem, accessed April 6, 2023 at https://pubchem.ncbi.nlm.nih.gov/

ANESTHETICS

Alpha-chloralose

Ketamine

Tiletamine

Zolazepam hydrochloride

SEDATIVES

Azaperone

Butorphanol

Butorphanol tartrate

Dexmedetomidine
APPENDIX 3. Chemical Structures. 111

Medetomidine HCl

Nalbuphine

Midazolam

Xylazine

TRANQUILIZERS

Acepromazine

ACCESSORY DRUGS/SUBSTANCES

Atipamezole HCl

Atropine

Atropine sulfate anhydrous
APPENDIX 3. Chemical Structures. 112

Doxapram

Naltrexone

Tolazoline hydrochloride

Yohimbine hydrochloride

EUTHANASIA AGENTS

Potassium chloride

Sodium pentobarbital
APPENDIX 3. Chemical Structures. 113
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